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1
Correia, Daniel V., Manuela Fogli, Kelly Hudspeth, Maria Gomes da Silva, Domenico Mavilio und Bruno Silva-Santos. „Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells“. Blood 118, Nr. 4 (28.07.2011): 992–1001. http://dx.doi.org/10.1182/blood-2011-02-339135.
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Abstract The success of cancer immunotherapy depends on productive tumor cell recognition by killer lymphocytes. γδ T cells are a population of innate-like lymphocytes endowed with strong, MHC-unrestricted cytotoxicity against tumor cells. This notwithstanding, we recently showed that a large proportion of human hematologic tumors is resistant to γδ peripheral blood lymphocytes (PBLs) activated with specific agonists to the highly prevalent Vγ9Vδ2 TCR. Although this probably constitutes an important limitation to current γδ T cell–mediated immunotherapy strategies, we describe here the differentiation of a novel subset of Vδ2− Vδ1+ PBLs expressing natural cytotoxicity receptors (NCRs) that directly mediate killing of leukemia cell lines and chronic lymphocytic leukemia patient neoplastic cells. We show that Vδ1+ T cells can be selectively induced to express NKp30, NKp44 and NKp46, through a process that requires functional phosphatidylinositol 3-kinase (PI-3K)/AKT signaling on stimulation with γc cytokines and TCR agonists. The stable expression of NCRs is associated with high levels of granzyme B and enhanced cytotoxicity against lymphoid leukemia cells. Specific gain-of-function and loss-of-function experiments demonstrated that NKp30 makes the most important contribution to TCR-independent leukemia cell recognition. Thus, NKp30+ Vδ1+ T cells constitute a novel, inducible and specialized killer lymphocyte population with high potential for immunotherapy of human cancer.
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García-Muñoz, Ricardo, María-Josefa Nájera, Jesús Feliu, Judith Antón-Remírez, Enrique Ramalle-Gómara, Raquel Marín-Gorricho, Raisa Peralta et al. „Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes’ army“. Future Science OA 5, Nr. 10 (01.12.2019): FSO425. http://dx.doi.org/10.2144/fsoa-2019-0064.
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Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.
3
Wallgren, A., R. Festin, C. Gidlof, M. Dohlsten, T. Kalland und TH Totterman. „Efficient killing of chronic B-lymphocytic leukemia cells by superantigen-directed T cells“. Blood 82, Nr. 4 (15.08.1993): 1230–38. http://dx.doi.org/10.1182/blood.v82.4.1230.1230.
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Abstract In vitro studies have indicated that chronic lymphocytic leukemia of B- cell origin (B-CLL) is resistant to cytotoxic effector lymphocytes such as natural killer and lymphokine activated killer (LAK) cells. We show here that B-cell cells are sensitive to Staphylococcal enterotoxin (SE) A-directed T-cell killing. Activation of the target cells by phorbol ester (tetradecanoyl phorbol acetate, [TPA]) greatly enhances their sensitivity to lysis. In SE-dependent cellular cytotoxicity (SDCC), members of the SE superantigen family form a bridge between T cells and target cells expressing major histocompatability complex class II molecules. Binding of SEA to the T-cell-receptor V beta region induces a strong cytotoxic capacity and cytokine production. Cells from 9 B-CLL patients were cultured in the presence or absence of TPA and used as targets in a 4-hour SDCC assay using an allogeneic T-cell line as effector. At an effector:target cell ratio 30:1, 70% to 80% of TPA- induced B-CLL cells were killed. Even at the effector:target ratio of 3:1, 47% +/- 6% of TPA-activated B-cell cells were lysed compared with 13% +/- 2% of resting cells (P < .001). A T-cell line established from a B-CLL patient killed autologous tumor cells as efficiently as allogeneic effectors. SEA-directed T cells were far more lytic to B-CLL cells compared with LAK cells or lectin (phytohemagglutinin-directed T cells. Mechanisms of SDCC lysis were investigated. Effector plus target cell supernatants contained high levels of tumor necrosis factor (TNF)- alpha and interferon-gamma, but these supernatants were not directly toxic to B-CLL cells in short term culture. High concentrations of recombinant TNF-alpha or TNF-beta had no lytic effect. Addition of neutralizing anti-TNF-alpha and anti-TNF-beta antibodies into the SDCC assay did not inhibit SEA-directed T-cell killing. TPA-activated B-CLL cells showed a 1.2- to 13-fold increased expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen (LFA)-1, and LFA-3, whereas expression of HLA class II molecules increased up to 5 times. The expression of CD72, CD40, and BB-1/B7 increased 1.8 to 4.5 times. The role of these surface molecules in SDCC was analyzed in blocking experiments with monoclonal antibodies. Antibodies to ICAM-1, CD18, and HLA-DR abolished the cytotoxicity, and a substantial reduction was seen with antibody to CD72.(ABSTRACT TRUNCATED AT 400 WORDS)
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Wallgren, A., R. Festin, C. Gidlof, M. Dohlsten, T. Kalland und TH Totterman. „Efficient killing of chronic B-lymphocytic leukemia cells by superantigen-directed T cells“. Blood 82, Nr. 4 (15.08.1993): 1230–38. http://dx.doi.org/10.1182/blood.v82.4.1230.bloodjournal8241230.
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In vitro studies have indicated that chronic lymphocytic leukemia of B- cell origin (B-CLL) is resistant to cytotoxic effector lymphocytes such as natural killer and lymphokine activated killer (LAK) cells. We show here that B-cell cells are sensitive to Staphylococcal enterotoxin (SE) A-directed T-cell killing. Activation of the target cells by phorbol ester (tetradecanoyl phorbol acetate, [TPA]) greatly enhances their sensitivity to lysis. In SE-dependent cellular cytotoxicity (SDCC), members of the SE superantigen family form a bridge between T cells and target cells expressing major histocompatability complex class II molecules. Binding of SEA to the T-cell-receptor V beta region induces a strong cytotoxic capacity and cytokine production. Cells from 9 B-CLL patients were cultured in the presence or absence of TPA and used as targets in a 4-hour SDCC assay using an allogeneic T-cell line as effector. At an effector:target cell ratio 30:1, 70% to 80% of TPA- induced B-CLL cells were killed. Even at the effector:target ratio of 3:1, 47% +/- 6% of TPA-activated B-cell cells were lysed compared with 13% +/- 2% of resting cells (P < .001). A T-cell line established from a B-CLL patient killed autologous tumor cells as efficiently as allogeneic effectors. SEA-directed T cells were far more lytic to B-CLL cells compared with LAK cells or lectin (phytohemagglutinin-directed T cells. Mechanisms of SDCC lysis were investigated. Effector plus target cell supernatants contained high levels of tumor necrosis factor (TNF)- alpha and interferon-gamma, but these supernatants were not directly toxic to B-CLL cells in short term culture. High concentrations of recombinant TNF-alpha or TNF-beta had no lytic effect. Addition of neutralizing anti-TNF-alpha and anti-TNF-beta antibodies into the SDCC assay did not inhibit SEA-directed T-cell killing. TPA-activated B-CLL cells showed a 1.2- to 13-fold increased expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen (LFA)-1, and LFA-3, whereas expression of HLA class II molecules increased up to 5 times. The expression of CD72, CD40, and BB-1/B7 increased 1.8 to 4.5 times. The role of these surface molecules in SDCC was analyzed in blocking experiments with monoclonal antibodies. Antibodies to ICAM-1, CD18, and HLA-DR abolished the cytotoxicity, and a substantial reduction was seen with antibody to CD72.(ABSTRACT TRUNCATED AT 400 WORDS)
5
Fehniger, Todd A., Kazuhiro Suzuki, Anand Ponnappan, Jeffrey B. VanDeusen, Megan A. Cooper, Sorin M. Florea, Aharon G. Freud, Michael L. Robinson, Joan Durbin und Michael A. Caligiuri. „Fatal Leukemia in Interleukin 15 Transgenic Mice Follows Early Expansions in Natural Killer and Memory Phenotype Cd8+ T Cells“. Journal of Experimental Medicine 193, Nr. 2 (15.01.2001): 219–32. http://dx.doi.org/10.1084/jem.193.2.219.
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Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. Later, these mice develop fatal lymphocytic leukemia with a T-NK phenotype. These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.
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Helfand, SC, JF Modiano, PF Moore, SA Soergel, PS MacWilliams, RD Dubielzig, JA Hank, EW Gelfand und PM Sondel. „Functional interleukin-2 receptors are expressed on natural killer-like leukemic cells from a dog with cutaneous lymphoma“. Blood 86, Nr. 2 (15.07.1995): 636–45. http://dx.doi.org/10.1182/blood.v86.2.636.bloodjournal862636.
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We identified a dog with large granular lymphocytic leukemia and cutaneous lymphoma that exhibited constitutive expression of interleukin-2 (IL-2) receptors by the leukemic peripheral blood lymphocytes. The leukemic cells phenotypically resembled natural killer (NK) cells, and their surface IL-2 receptors were functional, as determined by the capacity to bind human recombinant IL-2 with high- affinity resulting in the transduction of proliferation signals and in the development of lymphokine-activated killer cell activity. These cells produced IL-2 spontaneously, and they may have maintained their proliferative state through an IL-2-dependent autocrine growth pathway. Our results indicate that neoplastic lymphocytes of syndromes that involve circulating leukemic cells with dermotropism can originate from NK-like cells. Additionally, the data also suggest that proliferative conditions such as these may be the result of the aberrant production of IL-2. Further, this case illustrates the potential for the use of hematopoietic malignancies in the dog as a suitable animal model for immune targeting of IL-2 receptors as a novel treatment approach for similar malignancies of human beings.
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Ohmori, K., A. Takada, T. Yoneda, Y. Buma, K. Hirashima, K. Tsuyuoka, A. Hasegawa und R. Kannagi. „Differentiation-dependent expression of sialyl stage-specific embryonic antigen-1 and I-antigens on human lymphoid cells and its implications for carbohydrate-mediated adhesion to vascular endothelium“. Blood 81, Nr. 1 (01.01.1993): 101–11. http://dx.doi.org/10.1182/blood.v81.1.101.101.
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Abstract Expression of two developmentally regulated carbohydrate antigens, the sialyl stage-specific embryonic antigen-1 (SSEA-1) and I-antigens, in human lymphocytes and lymphocytic leukemia cells was investigated using specific monoclonal antibodies. Sialyl SSEA-1 was expressed only on natural killer (NK) cells, and was essentially absent on resting mature T and B cells among normal peripheral lymphocytes. On the other hand, the I-antigen was strongly expressed on virtually all mature B cells, moderately expressed on most mature T cells, but not expressed on NK cells in normal donors. Expression of the two antigens on normal T and B cells was reversible; in vitro stimulation of normal lymphocytes with concanavalin A (Con A) resulted in the loss of I-antigen and appearance of sialyl SSEA-1 on CD3+ T blasts, whereas stimulation with pokeweed mitogen led to loss of I-antigen expression and appearance of sialyl SSEA-1 antigen on CD19+ B blasts. Among lymphocytic leukemia cells, sialyl SSEA-1 was detected primarily on leukemia cells having immature properties such as most common acute lymphocytic leukemia (cALL) blasts, while the I-antigen was frequently expressed on malignant cells having relatively mature properties, such as those found in adult T- cell leukemia or chronic lymphocytic leukemia, and only occasionally on cALL blasts. Among normal peripheral lymphocytes, the sialyl SSEA-1+I- antigen- NK cells selectively underwent E-selectin (ELAM-1, endothelial- leukocyte adhesion molecule-1)-dependent adhesion to endothelial cells, while the I-antigen+sialyl SSEA-1- mature T and B cells did not, in line with the recent finding that sialyl SSEA-1 serves as a specific ligand for E-selectin. Con A blasts, which are sialyl SSEA-1+I-antigen- , also exhibited significant E-selectin-dependent adhesion to endothelial cells. These results indicate that expression of the sialyl SSEA-1 and I-antigens varies alternately depending on the differentiation/activation status of the lymphocytes, and that this at least partly regulates the behavior of lymphocytes at the vessel wall.
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Ohmori, K., A. Takada, T. Yoneda, Y. Buma, K. Hirashima, K. Tsuyuoka, A. Hasegawa und R. Kannagi. „Differentiation-dependent expression of sialyl stage-specific embryonic antigen-1 and I-antigens on human lymphoid cells and its implications for carbohydrate-mediated adhesion to vascular endothelium“. Blood 81, Nr. 1 (01.01.1993): 101–11. http://dx.doi.org/10.1182/blood.v81.1.101.bloodjournal811101.
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Expression of two developmentally regulated carbohydrate antigens, the sialyl stage-specific embryonic antigen-1 (SSEA-1) and I-antigens, in human lymphocytes and lymphocytic leukemia cells was investigated using specific monoclonal antibodies. Sialyl SSEA-1 was expressed only on natural killer (NK) cells, and was essentially absent on resting mature T and B cells among normal peripheral lymphocytes. On the other hand, the I-antigen was strongly expressed on virtually all mature B cells, moderately expressed on most mature T cells, but not expressed on NK cells in normal donors. Expression of the two antigens on normal T and B cells was reversible; in vitro stimulation of normal lymphocytes with concanavalin A (Con A) resulted in the loss of I-antigen and appearance of sialyl SSEA-1 on CD3+ T blasts, whereas stimulation with pokeweed mitogen led to loss of I-antigen expression and appearance of sialyl SSEA-1 antigen on CD19+ B blasts. Among lymphocytic leukemia cells, sialyl SSEA-1 was detected primarily on leukemia cells having immature properties such as most common acute lymphocytic leukemia (cALL) blasts, while the I-antigen was frequently expressed on malignant cells having relatively mature properties, such as those found in adult T- cell leukemia or chronic lymphocytic leukemia, and only occasionally on cALL blasts. Among normal peripheral lymphocytes, the sialyl SSEA-1+I- antigen- NK cells selectively underwent E-selectin (ELAM-1, endothelial- leukocyte adhesion molecule-1)-dependent adhesion to endothelial cells, while the I-antigen+sialyl SSEA-1- mature T and B cells did not, in line with the recent finding that sialyl SSEA-1 serves as a specific ligand for E-selectin. Con A blasts, which are sialyl SSEA-1+I-antigen- , also exhibited significant E-selectin-dependent adhesion to endothelial cells. These results indicate that expression of the sialyl SSEA-1 and I-antigens varies alternately depending on the differentiation/activation status of the lymphocytes, and that this at least partly regulates the behavior of lymphocytes at the vessel wall.
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Moignet, Aline, und Thierry Lamy. „Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia“. American Society of Clinical Oncology Educational Book, Nr. 38 (Mai 2018): 616–25. http://dx.doi.org/10.1200/edbk_200689.
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Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha–induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.
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Fricke, William. „CD11b Is Useful in the Diagnosis of Chronic Lymphocytic Leukemia/Prolymphocytic Leukemia, Mixed Chronic Lymphocytic Leukemia, and Prolymphocytic Leukemia.“ Blood 104, Nr. 11 (16.11.2004): 4806. http://dx.doi.org/10.1182/blood.v104.11.4806.4806.
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Abstract CD11b is well known as an integrin, Mac-1, is often complexed with CD18, and is found on monocytes, granulocytes, and natural killer cells. It also serves as a receptor for iC3b. However, its occurrence in B cell chronic lymphoproliferative disorders is not generally recognized and has not been fully evaluated. To address this issue, a series of B cell leukemias and lymphomas referred for primary diagnosis was evaluated for the presence of CD11b. The purpose was to determine the frequency of its expression on these tumors and to evaluate its diagnostic value. Consecutive cases referred for flow cytometry as possible lymphoproliferative disease were analyzed. Included were bone marrow, peripheral blood, and lymph nodes. All cases were diagnosed according to the WHO classification based on immunophenotypic, morphologic, and clinical findings. The morphologic criteria of Melo (1986) and Bennett (1989) were used for classification of chronic lymphocytic leukemia (CLL), CLL/prolymphocytic leukemia (CLL/PLL), mixed CLL, and PLL. Cases identified as not related to chronic lymphocytic leukemia or prolymphocytic leukemia were recorded but not further analyzed. Similarly, lymph node and spleen-based tumors were excluded from the final analysis. CD11b was present on cells from 32 of 123 cases, including occasional follicular lymphoma, (5/35); mantle cell lymphoma, (1/8); diffuse large B cell lymphoma, (3/9); hairy cell leukemia, (3/5); multiple myeloma, (1/2); lymphoplasmacytic lymphoma, (2/2); nodal marginal zone lymphoma, 0/1); and splenic marginal zone lymphoma, (1/1). However, it was most consistently expressed on CLL that contained increased numbers of prolymphocytes or large cells and on PLL. A total of 16 such cases were found. Morphologic assessment showed them to include 8 CLL/PLL, 3 mixed CLL, 4 PLL, and 1 typical CLL. The typical CLL case included both large cells and prolymphocytes but did not have more than 10% PLs. Five of the 16 cases (31%) were negative for CD5, CD23, and CD38 but were positive for FMC-7. In contrast, the other 11 cases were all CD5(+) and CD23(+); 3/11 were positive for CD38; and 5/11 were positive for FMC-7. Forty-five CLLs also were identified during the study, of which 27 had sufficient data for comparison. Twenty-six of the 27 CLLs were morphologically typical. The remaining case was mixed CLL. All of the CLLs were CD11b(−), CD5(+) and CD23(+); 15/43 were CD38(+), and 6/43 were FMC-7(+). The findings show that CD11b is expressed on chronic B cell lymphoproliferative disorders. In particular, it is expressed on almost all CLL cases that contain large cells or prolymphocytes and on PLL. Inclusion of CD11b in routine screening panels of possible chronic B cell leukemiaa will improve diagnosis of these disorders.
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Sheridan, W., EF Winton, WC Chan, DS Gordon, WR Vogler, C. Phillips, KF Bongiovanni und TA Waldmann. „Leukemia of non-T lineage natural killer cells“. Blood 72, Nr. 5 (01.11.1988): 1701–7. http://dx.doi.org/10.1182/blood.v72.5.1701.1701.
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Abstract An unusual case of an aggressive leukemia of natural killer (NK) cells occurred in a 65-year-old male. Clinical characteristics of this case included hepatosplenomegaly, ascites, marrow infiltrate with leukemic cells, and a WBC up to 82.8 X 10(9) before therapy. One year before his presentation he had been noted to have a WBC of 12.1 X 10(9) with 78% lymphocytes, and 6 months before had noted intermittent fever and weight loss. He and his brother had well documented hereditary cold urticaria. The patient was treated with a modification of ProMACE CYTABOM regimen and had prompt regression of the leukemia with associated acute tumor lysis. Renal, hepatic, and marrow failure predominated during a terminal course that ended 22 days after therapy was commenced, and at autopsy there was no evidence for leukemic cell infiltrate in the liver, spleen or marrow. The leukemic cells were large granular lymphocytes by light and electron microscopic criteria, and had the following immunophenotype: CD2+, DR+, Leu7+, NKH1+, CD11+, CD3-, CD5-, CD4-, CD8-, CD16-. The cells displayed high antibody- dependent cell-mediated cytotoxicity (ADCC) and NK activity, and had a high rate of spontaneous proliferation in vitro that was not augmented by phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). Southern analysis of DNA from leukemic cells revealed normal germline arrangements for the beta and gamma chains of the T cell antigen receptor and immunoglobulin heavy chain genes. The majority of metaphases were clonally abnormal revealing consistent rearrangements involving extra material attached to the long arms of chromosomes 5 and 11.
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Sheridan, W., EF Winton, WC Chan, DS Gordon, WR Vogler, C. Phillips, KF Bongiovanni und TA Waldmann. „Leukemia of non-T lineage natural killer cells“. Blood 72, Nr. 5 (01.11.1988): 1701–7. http://dx.doi.org/10.1182/blood.v72.5.1701.bloodjournal7251701.
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An unusual case of an aggressive leukemia of natural killer (NK) cells occurred in a 65-year-old male. Clinical characteristics of this case included hepatosplenomegaly, ascites, marrow infiltrate with leukemic cells, and a WBC up to 82.8 X 10(9) before therapy. One year before his presentation he had been noted to have a WBC of 12.1 X 10(9) with 78% lymphocytes, and 6 months before had noted intermittent fever and weight loss. He and his brother had well documented hereditary cold urticaria. The patient was treated with a modification of ProMACE CYTABOM regimen and had prompt regression of the leukemia with associated acute tumor lysis. Renal, hepatic, and marrow failure predominated during a terminal course that ended 22 days after therapy was commenced, and at autopsy there was no evidence for leukemic cell infiltrate in the liver, spleen or marrow. The leukemic cells were large granular lymphocytes by light and electron microscopic criteria, and had the following immunophenotype: CD2+, DR+, Leu7+, NKH1+, CD11+, CD3-, CD5-, CD4-, CD8-, CD16-. The cells displayed high antibody- dependent cell-mediated cytotoxicity (ADCC) and NK activity, and had a high rate of spontaneous proliferation in vitro that was not augmented by phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). Southern analysis of DNA from leukemic cells revealed normal germline arrangements for the beta and gamma chains of the T cell antigen receptor and immunoglobulin heavy chain genes. The majority of metaphases were clonally abnormal revealing consistent rearrangements involving extra material attached to the long arms of chromosomes 5 and 11.
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Sportoletti, Paolo, Filomena De Falco, Beatrice Del Papa, Stefano Baldoni, Valerio Guarente, Andrea Marra, Erica Dorillo et al. „NK Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications“. International Journal of Molecular Sciences 22, Nr. 13 (22.06.2021): 6665. http://dx.doi.org/10.3390/ijms22136665.
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Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.
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Link, DC, und M. Zutter. „The proto-oncogene c-fgr is expressed in normal mantle zone B lymphocytes and is developmentally regulated during myelomonocytic differentiation in vivo“. Blood 85, Nr. 2 (15.01.1995): 472–79. http://dx.doi.org/10.1182/blood.v85.2.472.472.
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Abstract The proto-oncogene c-fgr is a member of the c-src gene family of cytoplasmic tyrosine kinases. Previous studies have suggested that it is normally expressed in neutrophils, monocytes, macrophages, and natural killer cells. c-fgr is also expressed in the B cells of certain lymphoproliferative disorders, namely, Epstein-Barr virus-associated lymphoproliferative disease, and in chronic lymphocytic leukemia, but it has not previously been detected in normal or reactive human lymphoid tissue. In this study we have determined the pattern of p55c- fgr protein expression in normal human hematopoietic and lymphoid tissues at the single-cell level using immunohistochemical and immunofluorescent techniques. We show that p55c-fgr expression is developmentally regulated with high-level expression first evident at the myelocyte stage of myeloid differentiation. In addition, we show that p55c-fgr is expressed in circulating B lymphocytes isolated from chronic lymphocytic leukemia patients but is not expressed in normal circulating B lymphocytes. Surprisingly, p55c-fgr is also expressed in a subpopulation of normal B lymphocytes, the mantle zone B lymphocytes. This demonstration that p55c-fgr is expressed in a normal B-lymphocyte subpopulation suggests that its expression in certain B-cell lymphoproliferative disorders may be an indirect consequence of, rather than a primary cause of, the neoplastic transformation process.
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Link, DC, und M. Zutter. „The proto-oncogene c-fgr is expressed in normal mantle zone B lymphocytes and is developmentally regulated during myelomonocytic differentiation in vivo“. Blood 85, Nr. 2 (15.01.1995): 472–79. http://dx.doi.org/10.1182/blood.v85.2.472.bloodjournal852472.
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The proto-oncogene c-fgr is a member of the c-src gene family of cytoplasmic tyrosine kinases. Previous studies have suggested that it is normally expressed in neutrophils, monocytes, macrophages, and natural killer cells. c-fgr is also expressed in the B cells of certain lymphoproliferative disorders, namely, Epstein-Barr virus-associated lymphoproliferative disease, and in chronic lymphocytic leukemia, but it has not previously been detected in normal or reactive human lymphoid tissue. In this study we have determined the pattern of p55c- fgr protein expression in normal human hematopoietic and lymphoid tissues at the single-cell level using immunohistochemical and immunofluorescent techniques. We show that p55c-fgr expression is developmentally regulated with high-level expression first evident at the myelocyte stage of myeloid differentiation. In addition, we show that p55c-fgr is expressed in circulating B lymphocytes isolated from chronic lymphocytic leukemia patients but is not expressed in normal circulating B lymphocytes. Surprisingly, p55c-fgr is also expressed in a subpopulation of normal B lymphocytes, the mantle zone B lymphocytes. This demonstration that p55c-fgr is expressed in a normal B-lymphocyte subpopulation suggests that its expression in certain B-cell lymphoproliferative disorders may be an indirect consequence of, rather than a primary cause of, the neoplastic transformation process.
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Zhang, Dan, und Thomas P. Loughran. „Large granular lymphocytic leukemia: molecular pathogenesis, clinical manifestations, and treatment“. Hematology 2012, Nr. 1 (08.12.2012): 652–59. http://dx.doi.org/10.1182/asheducation.v2012.1.652.3798658.
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Abstract Large granular lymphocyte (LGL) leukemia represents a spectrum of rare lymphoproliferative diseases defined by clonal amplification of either CD3+ cytotoxic T-lymphocytes or CD3− natural killer cells. This chapter focuses on the T-cell form of LGL leukemia. Clinical features include neutropenia, anemia, and rheumatoid arthritis. LGL leukemia is thought to arise from chronic antigenic stimulation, with the long-term survival of LGL being promoted by constitutive activation of multiple survival signaling pathways, such as the JAK/STAT3, sphingolipid, and Ras/MEK/ERK pathways. Therefore, these lead to global deregulation of apoptosis and resistance to normal pathways of activation-induced cell death. The majority of LGL leukemia patients eventually need treatment. Treatment of leukemic LGL is based on immunosuppressive therapy, primarily using low doses of methotrexate or cyclophosphamide. However, no standard therapy has been established because of the lack of large, prospective trials. In addition, because some patients are refractory to currently available treatments and none of these therapeutic modalities can cure LGL leukemia, new therapeutic options are needed. Understanding the current state of the pathogenesis of LGL leukemia may provide insights into novel therapeutic options.
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Svanberg, Rebecka, Sine Janum, Piers E. M. Patten, Alan G. Ramsay und Carsten U. Niemann. „Targeting the tumor microenvironment in chronic lymphocytic leukemia“. Haematologica 106, Nr. 9 (22.04.2021): 2312–24. http://dx.doi.org/10.3324/haematol.2020.268037.
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The tumor microenvironment (TME) plays an essential role in the development, growth, and survival of the malignant B-cell clone in chronic lymphocytic leukemia (CLL). Within the proliferation niches of lymph nodes, bone marrow, and secondary lymphoid organs, a variety of phenotypically and functionally altered cell types, including T cells, natural killer cells, monocytes/macrophages, endothelial and mesenchymal stroma cells, provide crucial survival signals, along with CLL-cellinduced suppression of antitumor immune responses. The B-cell receptor pathway plays a pivotal role in mediating the interaction between CLL cells and the TME. However, an increasing number of additional components of the multifactorial TME are being discovered. Although the majority of therapeutic strategies employed in CLL hitherto have focused on targeting the leukemic cells, emerging evidence implies that modulation of microenvironmental cells and CLL-TME interactions by novel therapeutic agents significantly affect their clinical efficacy. Thus, improving our understanding of CLL-TME interactions and how they are affected by current therapeutic agents may improve and guide treatment strategies. Identification of novel TME interactions may also pave the road for the development of novel therapeutic strategies targeting the TME. In this review, we summarize current evidence on the effects of therapeutic agents on cells and interactions within the TME. With a growing demand for improved and personalized treatment options in CLL, this review aims at inspiring future exploration of smart drug combination strategies, translational studies, and novel therapeutic targets in clinical trials.
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Tagawa, S., M. Hatakeyama, M. Shibano, T. Taniguchi und T. Kitani. „The expression of the p75 subunit of interleukin 2 receptor in Tac negative leukemic cells of two patients with large granular lymphocytic leukemia“. Blood 71, Nr. 4 (01.04.1988): 1161–64. http://dx.doi.org/10.1182/blood.v71.4.1161.1161.
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Abstract The expression of interleukin 2 receptor (IL-2R) on leukemic cells of natural killer (NK) and T cell lineages in two patients with large granular lymphocytic (LGL) leukemia was examined. The p55 Tac IL-2R was not detected by the indirect immunofluorescence method and it did not participate in the IL-2 binding to the surface of these cells. However, these leukemic cells proliferated in a IL-2 dose-dependent manner and expressed p55. A p75 IL-2 receptor (IL-2-R) subunit was detected on the LGL leukemic cells of both NK and T lineages in a crosslink assay. Thus, it is suggested that the primary signal of IL-2 is mediated by the p75 alone. A study of the inhibitions of the proliferative response of LGL leukemia cells by anti-Tac revealed that both p75 and secondarily induced p55 are required for the cell proliferation.
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Tagawa, S., M. Hatakeyama, M. Shibano, T. Taniguchi und T. Kitani. „The expression of the p75 subunit of interleukin 2 receptor in Tac negative leukemic cells of two patients with large granular lymphocytic leukemia“. Blood 71, Nr. 4 (01.04.1988): 1161–64. http://dx.doi.org/10.1182/blood.v71.4.1161.bloodjournal7141161.
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The expression of interleukin 2 receptor (IL-2R) on leukemic cells of natural killer (NK) and T cell lineages in two patients with large granular lymphocytic (LGL) leukemia was examined. The p55 Tac IL-2R was not detected by the indirect immunofluorescence method and it did not participate in the IL-2 binding to the surface of these cells. However, these leukemic cells proliferated in a IL-2 dose-dependent manner and expressed p55. A p75 IL-2 receptor (IL-2-R) subunit was detected on the LGL leukemic cells of both NK and T lineages in a crosslink assay. Thus, it is suggested that the primary signal of IL-2 is mediated by the p75 alone. A study of the inhibitions of the proliferative response of LGL leukemia cells by anti-Tac revealed that both p75 and secondarily induced p55 are required for the cell proliferation.
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Hofland, Tom, Eric Eldering, Arnon P. Kater und Sanne H. Tonino. „Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia“. International Journal of Molecular Sciences 20, Nr. 17 (03.09.2019): 4315. http://dx.doi.org/10.3390/ijms20174315.
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Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction. CLL cells affect the phenotype and function of the entire spectrum of innate and adaptive immune cells, including monocytes, T cells, and natural killer (NK) cells, leading to a tumor-supportive environment and reduced immunosurveillance. Novel immunotherapies like immune checkpoint blockade, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) T cells use the patients’ immune system to induce therapeutic responses. Although these novel immunotherapies showed impressive results in several B cell lymphomas, responses in CLL were often disappointing. The strong immunomodulatory effect of CLL is believed to play a pivotal role in the low response rates to these immunotherapeutic strategies. In this review, we summarize how CLL influences the function of non-malignant lymphocytes, with a special focus on T and NK cells, two important cellular mediators for immunotherapy. Secondly, we provide a short overview of the activity of several immunotherapeutics in CLL, and discuss how novel strategies may overcome the disappointing response rates in CLL.
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Foa, R., MT Fierro, D. Raspadori, M. Bonferroni, S. Cardona, A. Guarini, AG Tos, PF di Celle, A. Cesano und L. Matera. „Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors“. Blood 76, Nr. 7 (01.10.1990): 1349–54. http://dx.doi.org/10.1182/blood.v76.7.1349.1349.
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Abstract The capacity to generate lymphokine-activated killer (LAK) cells and the susceptibility of the neoplastic cells to both allogeneic and autologous LAK effectors were studied in B and T chronic lymphoproliferative disorders. While in B-cell chronic lymphocytic leukemia (B-CLL) the depressed natural killer function could be restored after a 7-day incubation with recombinant interleukin (IL-2), B-CLL mononuclear cells showed a reduced LAK activity compared with normal LAK cells. Furthermore, in all but 1 of the 20 B-CLL samples tested the leukemic cells were totally resistant to autologous LAK effectors. In most cases the leukemic cells were also resistant to normal allogeneic LAK cells. Competition experiments demonstrated that the patients' LAK cells, as well as normal LAK effectors, were capable of recognizing B-CLL cells, pointing, therefore, to a postbinding cytolytic defect. In hairy cell leukemia (HCL) an overall reduced LAK activity against allogeneic targets was documented, but, at variance from B-CLL, hairy cells were often susceptible to the lytic effect of normal LAK cells, and in half of the cases tested the neoplastic population was also sensitive in an autologous system. Similarly to B- CLL, in the great majority of T chronic lymphoproliferative disorders studied, the pathologic cells were resistant to normal and autologous LAK effectors and a defective LAK generation was found. These results demonstrate that in most B and T chronic leukemias the LAK function is defective and, when inducible, does not appear directed against the leukemic population. The possibility of exploiting an immunotherapeutic approach with IL-2/LAK cells in the management of chronic lymphoproliferative disorders does not gain support by these findings.
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Foa, R., MT Fierro, D. Raspadori, M. Bonferroni, S. Cardona, A. Guarini, AG Tos, PF di Celle, A. Cesano und L. Matera. „Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors“. Blood 76, Nr. 7 (01.10.1990): 1349–54. http://dx.doi.org/10.1182/blood.v76.7.1349.bloodjournal7671349.
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The capacity to generate lymphokine-activated killer (LAK) cells and the susceptibility of the neoplastic cells to both allogeneic and autologous LAK effectors were studied in B and T chronic lymphoproliferative disorders. While in B-cell chronic lymphocytic leukemia (B-CLL) the depressed natural killer function could be restored after a 7-day incubation with recombinant interleukin (IL-2), B-CLL mononuclear cells showed a reduced LAK activity compared with normal LAK cells. Furthermore, in all but 1 of the 20 B-CLL samples tested the leukemic cells were totally resistant to autologous LAK effectors. In most cases the leukemic cells were also resistant to normal allogeneic LAK cells. Competition experiments demonstrated that the patients' LAK cells, as well as normal LAK effectors, were capable of recognizing B-CLL cells, pointing, therefore, to a postbinding cytolytic defect. In hairy cell leukemia (HCL) an overall reduced LAK activity against allogeneic targets was documented, but, at variance from B-CLL, hairy cells were often susceptible to the lytic effect of normal LAK cells, and in half of the cases tested the neoplastic population was also sensitive in an autologous system. Similarly to B- CLL, in the great majority of T chronic lymphoproliferative disorders studied, the pathologic cells were resistant to normal and autologous LAK effectors and a defective LAK generation was found. These results demonstrate that in most B and T chronic leukemias the LAK function is defective and, when inducible, does not appear directed against the leukemic population. The possibility of exploiting an immunotherapeutic approach with IL-2/LAK cells in the management of chronic lymphoproliferative disorders does not gain support by these findings.
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Gowda, A. C., A. Ramanunni, C. Cheney, J. Roda, W. Kindsvogel, D. Henderson, S. pallavur, W. Carson, N. Muthusamy und J. C. Byrd. „IL-21 enhances chemoimmunotherapy mediated death of chronic lymphocytic leukemia cells“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 7094. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7094.
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7094 Chemoimmunotherapy with fludarabine and rituximab has demonstrated promising clinical activity in CLL. We hypothesized that the IL-21 might enhance the efficacy of this regimen and play a role in immune mediated clearance of CLL cells. Expression of IL21R-a was present (>20% cells +) in 13 of 16 (81%) pts. IL-21 induced direct cytotoxicity of CLL cells (>20% apoptosis) in subset of patients (n=9, 40% ± 15.9, p<0.0001) that directly correlates with expression of surface IL-21 receptor-a (p=0.001). This direct apoptotic effect is time dependent with maximum cytotoxicity observed at 72 hours post treatment at 25ng/ml. IL-21 induced phosphorylation of STAT-1tyr- 701 and STAT-3tyr-705 was seen in cells with apoptosis >20% whereas phosphorylation of STAT-1tyr-701 was not seen in cells failing to undergo apoptosis. In contrast to this, responder and non responder cells exhibited comparable levels of STAT-1, STAT-3 and constitutive Ser727 phosphorylated STAT-3 levels. Further, IL-21 induced upregulation of Bim was observed in the cells undergoing apoptosis. Interestingly, IL-21 enhanced additively, the direct apoptosis by either antibody (rituximab or alemtuzumab) or fludarabine therapy (Pretreatment of CLL cells with IL-21 for 18–20 hours). In contrast to the enhanced fludarabine mediated direct cytotoxic death of B cells, IL-21 failed to enhance the fludarabine mediated death of T cells (n=5, % alive 56±15 vs 58±16 with IL-21) suggesting that this immunotherapeutic strategy will not augment the immunosuppressive effect of fludarabine. IL-21 also enhanced innate immune activation as demonstrated by killer inhibitory receptor matched autologous natural killer cell mediated antibody dependent cellular cytotoxicity against rituximab coated CLL cells by 33% (E: T ratio 25:1, 42% ± 4.4 versus 28% ± 3.1, p<0.0001). In conclusion, our data demonstrates that IL-21 1) enhances autologous CLL NK cell function against rituximab coated tumor cells 2) mediate direct apoptotic signaling that correlates with STAT1 signaling and BIM up-regulation, and 3) enhance sensitivity to both fludarabine and rituximab mediated direct apoptosis. These results provide strong support for future clinical investigation of IL-21 as a single agent and as part of chemoimmunotherapy regimens for CLL. No significant financial relationships to disclose.
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Liu, Xin, Lindsay Ryland, Jun Yang, Aijun Liao, Cesar Aliaga, Rebecca Watts, Su-Fern Tan et al. „Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia“. Blood 116, Nr. 20 (18.11.2010): 4192–201. http://dx.doi.org/10.1182/blood-2010-02-271080.
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Abstract The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C6-ceramide (C6) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time- and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C6-ceramide may be a promising therapeutic approach for a fatal leukemia.
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Ibrahim, Uroosa, Sara Parylo, Shiksha Kedia, Shafinaz Hussein und Jean Paul Atallah. „Large Granular Lymphocytic Leukemia: A Report of Response to Rituximab“. Case Reports in Hematology 2017 (2017): 1–3. http://dx.doi.org/10.1155/2017/7506542.
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Large granular lymphocytic (LGL) leukemia is a rare form of low grade leukemia characterized by large cytotoxic T cells or natural killer cells on morphological examination. Immunosuppressive therapy is employed as first-line therapy. Treatment options in refractory cases include the anti-CD52 antibody alemtuzumab and purine analogues. We report a rare case that responded to the anti-CD20 monoclonal antibody rituximab. A 77-year-old female presented with complaints of fatigue, fever, and chills of 3 months’ duration. A CBC showed that pancytopenia with an absolute neutrophil count (ANC) was 0. Peripheral blood flow cytometry detected increased number of T cell large granular lymphocytes and T cell receptor rearrangement study detected a clonal T cell population. Bone marrow biopsy showed peripheral T cell lymphoma, most consistent with T-large granulocytic leukemia. The patient was treated with prednisone and oral cyclophosphamide for four months with no response. Thereafter, she received four weekly infusions of rituximab with improvement in her blood counts. A response to rituximab in refractory cases such as ours has been reported and may guide us towards exploring other immune-based therapeutics in this rare disease.
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Hercend, T., T. Takvorian, A. Nowill, R. Tantravahi, P. Moingeon, KC Anderson, C. Murray, C. Bohuon, A. Ythier und J. Ritz. „Characterization of natural killer cells with antileukemia activity following allogeneic bone marrow transplantation“. Blood 67, Nr. 3 (01.03.1986): 722–28. http://dx.doi.org/10.1182/blood.v67.3.722.722.
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Abstract To identify cells with potential antileukemia activity following bone marrow transplantation, we have monitored immunologic reconstitution in a patient with acute lymphocytic leukemia in second remission who received intensive chemotherapy and total body irradiation followed by infusion of allogeneic histocompatible marrow. Prior to transplantation, donor bone marrow cells were depleted of T lymphocytes by in vitro treatment with anti-T12 monoclonal antibody and rabbit complement. In the first 3 weeks following bone marrow transplantation, the predominant regenerating mononuclear cell population in peripheral blood exhibited a phenotype characteristic of natural killer (NK) cells. After 4 weeks, T lymphocytes became predominant, but NK cells persisted. Cultured peripheral blood lymphocytes obtained 12 weeks posttransplant were able to display significant cytotoxicity against leukemic blasts that had been cryopreserved at the time of relapse 5 months prior to bone marrow transplantation. To further characterize those cells with antileukemia activity, we used in vitro cloning techniques to identify four monoclonal populations, termed TC12, -48, - 50, and -59, with strong antitumor activity. Cytogenetic analysis demonstrated that each clone was of donor origin. Phenotypic characterization showed that the four clones expressed NKH1A but did not express T3, T4, or T8 antigens. Three of the four clones expressed T11/E rosette antigen. Each clone exhibited strong cytotoxicity against genetically unrelated hematopoietic tumor cell lines such as K562, Molt- 4, JM, and U937. In addition, we found that these patient clones were similar to cloned NK cells previously derived from normal individuals. Taken together, these results suggest that at least some clones with antileukemia activity following bone marrow transplantation are cells with NK-like function and phenotype. Functional analysis of these cytolytic cells in larger numbers of patients will be necessary to determine the clinical significance of this finding.
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Hercend, T., T. Takvorian, A. Nowill, R. Tantravahi, P. Moingeon, KC Anderson, C. Murray, C. Bohuon, A. Ythier und J. Ritz. „Characterization of natural killer cells with antileukemia activity following allogeneic bone marrow transplantation“. Blood 67, Nr. 3 (01.03.1986): 722–28. http://dx.doi.org/10.1182/blood.v67.3.722.bloodjournal673722.
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To identify cells with potential antileukemia activity following bone marrow transplantation, we have monitored immunologic reconstitution in a patient with acute lymphocytic leukemia in second remission who received intensive chemotherapy and total body irradiation followed by infusion of allogeneic histocompatible marrow. Prior to transplantation, donor bone marrow cells were depleted of T lymphocytes by in vitro treatment with anti-T12 monoclonal antibody and rabbit complement. In the first 3 weeks following bone marrow transplantation, the predominant regenerating mononuclear cell population in peripheral blood exhibited a phenotype characteristic of natural killer (NK) cells. After 4 weeks, T lymphocytes became predominant, but NK cells persisted. Cultured peripheral blood lymphocytes obtained 12 weeks posttransplant were able to display significant cytotoxicity against leukemic blasts that had been cryopreserved at the time of relapse 5 months prior to bone marrow transplantation. To further characterize those cells with antileukemia activity, we used in vitro cloning techniques to identify four monoclonal populations, termed TC12, -48, - 50, and -59, with strong antitumor activity. Cytogenetic analysis demonstrated that each clone was of donor origin. Phenotypic characterization showed that the four clones expressed NKH1A but did not express T3, T4, or T8 antigens. Three of the four clones expressed T11/E rosette antigen. Each clone exhibited strong cytotoxicity against genetically unrelated hematopoietic tumor cell lines such as K562, Molt- 4, JM, and U937. In addition, we found that these patient clones were similar to cloned NK cells previously derived from normal individuals. Taken together, these results suggest that at least some clones with antileukemia activity following bone marrow transplantation are cells with NK-like function and phenotype. Functional analysis of these cytolytic cells in larger numbers of patients will be necessary to determine the clinical significance of this finding.
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Sordo-Bahamonde, Christian, Seila Lorenzo-Herrero, Ana P. Gonzalez-Rodriguez, Ángel R. Payer, Esther González-García, Alejandro López-Soto und Segundo Gonzalez. „BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia“. Cancers 13, Nr. 8 (07.04.2021): 1766. http://dx.doi.org/10.3390/cancers13081766.
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Chronic lymphocytic leukemia (CLL) is characterized by progressive immunosuppression and diminished cancer immunosurveillance. Immune checkpoint blockade (ICB)-based therapies, a major breakthrough against cancer, have emerged as a powerful tool to reinvigorate antitumor responses. Herein, we analyzed the role of the novel inhibitory checkpoint BTLA and its ligand, HVEM, in the regulation of leukemic and natural killer (NK) cells in CLL. Flow cytometry analyses showed that BTLA expression is upregulated on leukemic cells and NK cells from patients with CLL, whereas HVEM is downregulated only in leukemic cells, especially in patients with advanced Rai-Binet stage. In silico analysis revealed that increased HVEM, but not BTLA, mRNA expression in leukemic cells correlated with diminished overall survival. Further, soluble BTLA (sBTLA) was found to be increased in the sera of patients with CLL and highly correlated with poor prognostic markers and shorter time to treatment. BTLA blockade with an anti-BTLA monoclonal antibody depleted leukemic cells and boosted NK cell-mediated responses ex vivo by increasing their IFN-γ production, cytotoxic capability, and antibody-dependent cytotoxicity (ADCC). In agreement with an inhibitory role of BTLA in NK cells, surface BTLA expression on NK cells was associated with poor outcome in patients with CLL. Overall, this study is the first to bring to light a role of BTLA/HVEM in the suppression of NK cell-mediated immune responses in CLL and its impact on patient’s prognosis, suggesting that BTLA/HVEM axis may be a potential therapeutic target in this disease.
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Fauriat, Cyril, Alessandro Moretta, Daniel Olive und Régis T. Costello. „Defective killing of dendritic cells by autologous natural killer cells from acute myeloid leukemia patients“. Blood 106, Nr. 6 (15.09.2005): 2186–88. http://dx.doi.org/10.1182/blood-2005-03-1270.
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Abstract At the frontier between innate and adaptive immunity, dendritic cells (DCs) secrete numerous cytokines and express costimulatory molecules that initiate or enhance natural killer (NK) and T-lymphocyte responses. NK cells also regulate DC physiology by killing immature DCs (iDCs), thus limiting inflammation and inappropriate T-lymphocyte tolerization. In a previous study, we have reported that NK cells from acute myeloid leukemia patients (AML-NK cells) have deficient natural cytotoxicity receptor (NCR) expression. Herein, we analyzed the consequences of such a defect regarding the regulatory role of AML-NK cells in DC physiology. We show that NK cells display poor cytolytic capacities against DCs derived from healthy donor monocytes or derived from autologous leukemic blasts. These data point to a novel defect in the regulation of adaptive immune responses initiated by DCs in AML patients. This may lead to specific T-lymphocyte tolerization by spontaneous or ex vivo expanded iDCs expressing leukemia-derived antigens. (Blood. 2005;106: 2186-2188)
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Ziegler-Heitbrock, HW, H. Rumpold, D. Kraft, C. Wagenpfeil, R. Munker, T. Abo, CM Balch und TW LeBien. „Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation“. Blood 65, Nr. 1 (01.01.1985): 65–70. http://dx.doi.org/10.1182/blood.v65.1.65.65.
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Abstract Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.
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Ziegler-Heitbrock, HW, H. Rumpold, D. Kraft, C. Wagenpfeil, R. Munker, T. Abo, CM Balch und TW LeBien. „Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation“. Blood 65, Nr. 1 (01.01.1985): 65–70. http://dx.doi.org/10.1182/blood.v65.1.65.bloodjournal65165.
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Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.
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Liu, Xin, Lindsay Ryland, Jun Yang, Cesar Aliaga, James Kaiser, Ranran Zhang, Kendall Thomas et al. „Systemic Delivery of Nanoliposomal Ceramide Displays Anti-Leukemic Activity in a Rat Model of Large Granular Lymphocytic Leukemia“. Blood 112, Nr. 11 (16.11.2008): 3999. http://dx.doi.org/10.1182/blood.v112.11.3999.3999.
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Abstract We have previously demonstrated that enhanced survival rather than increased proliferation accounts for the accumulation of natural killer (NK) cells in large granular lymphocyte (LGL) leukemia patients. To further elucidate the mechanism by which NK survival is enhanced, we analyzed leukemic NK cells isolated either from patient peripheral blood or rat splenic cells for altered expression of members of the inhibitor of apoptosis protein (IAP) family, which act as suppressors of apoptosis in a variety of human solid tumors and hematological malignancies. We now report that the IAP, survivin, was highly expressed in NK cells. In contrast, survivin was barely detectable in NK cells from the blood of normal human donors or the splenic cells from normal rats. We next asked if the lipid-derived second messenger, ceramide, which selectively induces apoptosis in cancer cells would diminish survivin protein expression. Treatment of NKL, a human NK-LGL leukemia cell line, or RNK-16, a rat NK-LGL leukemia cell line, with the cell-permeable, short-chain C6-ceramide (C6) in a pegylated liposomal formulation, led to cell apoptosis and diminished survivin protein expression, in a time and dose dependent manner. We next extended these in vitro studies to an in vivo rat model of NK-LGL leukemia. Systemic i.v. delivery of liposomal ceramide displayed significant anti-leukemia activity in a syngeneic Fischer F344 rat NK-LGL leukemia model that exhibits clonal expansion of CD3-CD8a+ lymphocytes. Over a 6-week treatment period, a well-tolerated dose of 40 mg/kg liposomal-C6, three times a week, elicited a 3 to 10- fold reduction in the weight of various lymphoid and non-lymphoid organs, compared with liposomal formulations that did not contain ceramide (ghost). Untreated or ghost-treated leukemic rats presented with lymphocytosis (LGL counts between 2 × 1011 and 3.5 × 1011/L), anemia and thrombocytopenia. Furthermore, the percentage of NK LGL cells, defined as CD3-CD8a+ by flow cytometry, was drastically elevated in the spleen, lymph node, thymus, bone marrow, blood, liver and lung in these leukemic rats, compared with their normal counterparts. In contrast, leukemic rats treated with liposomal ceramide had undetectable LGL cells in the blood and normal counts of red blood cells and platelets. Additionally, the CD3-CD8a+ NK cells in spleen, thymus and liver were found to be remarkably decreased, whereas the NK cells in bone marrow, blood and lung were within normal range. Collectively, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for anti-leukemic efficacy in a rat model of NK LGL leukemia, possibly via decreased survivin expression or signaling.
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Fais, Franco, Fortunato Morabito, Caterina Stelitano, Vincenzo Callea, Sabrina Zanardi, Marco Scudeletti, Paola Varese, Ermanno Ciccone und Carlo Enrico Grossi. „CD1d is expressed on B-chronic lymphocytic leukemia cells and mediates ?-galactosylceramide presentation to natural killer T lymphocytes“. International Journal of Cancer 109, Nr. 3 (2004): 402–11. http://dx.doi.org/10.1002/ijc.11723.
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Jerez, Andres, Michael J. Clemente, Hideki Makishima, Hanna Koskela, Francis LeBlanc, Kwok Peng Ng, Thomas Olson et al. „STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia“. Blood 120, Nr. 15 (11.10.2012): 3048–57. http://dx.doi.org/10.1182/blood-2012-06-435297.
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AbstractChronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions.
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Saudemont, Aurore, Nathalie Jouy, Dominique Hetuin und Bruno Quesnel. „NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells“. Blood 105, Nr. 6 (15.03.2005): 2428–35. http://dx.doi.org/10.1182/blood-2004-09-3458.
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AbstractTumor dormancy is a phenomenon where small numbers of tumor cells persist in the host for months or years. We previously showed in the DA1-3b/C3H mouse model of acute myeloid leukemia that dormant tumor cells resist cytotoxic T-lymphocyte (CTL)–mediated killing because they overexpress B7-H1. Here, we vaccinated mice with DA1-3b cells transduced with CXCL10. Vaccinated mice developed a strong systemic immunity that led to the cure of established leukemia without persistence of dormant tumor cells. In vivo depletion of natural killer (NK) cells from the mice abrogated the protective effect of the vaccine. Long-term persistent leukemic cells resist CTL-mediated lysis but were killed by NK cells from mice vaccinated with DA1-3b/CXCL10. These NK cells expressed B7-H1. Recombinant CXCL10, CXCL9, CXCL11, and CXCL12 chemokines induced expression of B7-H1 on mouse and human NK cells in vitro. Mouse and human B7-H1+ NK cells induced proliferation of T cells and production of interferon γ and tumor necrosis factor α in vitro, and in vivo blocking of B7-H1 inhibited the protective effect of vaccination. Thus, CXCL10 induces antileukemic immunity, at least partially by stimulating NK cells to express B7-H1+. This antitumor effect is in contrast to the effect of B7-H1 when expressed on tumor cells because it stops cytotoxic lymphocytes from killing those tumor cells.
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Tagawa, S., Y. Tokumine, E. Ueda, K. Waki, Y. Kanayama, N. Taniguchi, T. Nakanishi, R. Inoue und T. Kitani. „Leu 11+ T gamma cell chronic lymphocytic leukemia with partially activated natural killer function and its further activation by recombinant IL2 in vitro“. Blood 68, Nr. 4 (01.10.1986): 846–52. http://dx.doi.org/10.1182/blood.v68.4.846.846.
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Abstract A patient with T gamma cell chronic lymphocytic leukemia with the Leu 11+ phenotype and novel function of activated natural killer cells is reported. The peripheral blood mononuclear cells of this patient showed large granular lymphocytes by May-Giemsa staining and lamellipodia by scanning electron micrography. Tests on reactivity with monoclonal antibodies showed that most cells were Leu 11+, OKT3-/Leu 1-, OKT4-, OKT8-, Leu 7-, OKM1-, and Tac-. Freshly collected cells lysed not only K562, which is highly sensitive to natural killer cells, but also Raji cells and Daudi cells, which are not. Leu 11+ cells were triggered by recombinant interleukin 2 (rIL2) to proliferate, produce gamma- interferon (gamma IFN), and show enhanced HLA-DR antigen expression, and 30% of the Leu 11+ cells became positive for IL2 receptor antigen (Tac). The spectrum of cytotoxic activity of these cells against target cells was extended by rIL2; after treatment with rIL2, the cells also lysed HeLa cells and even fresh cancer cells. This stimulation also increased the activities of acid phosphatase and tartrate-resistant acid phosphatase of the cells and resulted in the appearance of nonspecific esterase activity. The expanded cell population may represent a neoplasm, but these findings provide information on a novel differentiation stage of activated NK cells.
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Tagawa, S., Y. Tokumine, E. Ueda, K. Waki, Y. Kanayama, N. Taniguchi, T. Nakanishi, R. Inoue und T. Kitani. „Leu 11+ T gamma cell chronic lymphocytic leukemia with partially activated natural killer function and its further activation by recombinant IL2 in vitro“. Blood 68, Nr. 4 (01.10.1986): 846–52. http://dx.doi.org/10.1182/blood.v68.4.846.bloodjournal684846.
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A patient with T gamma cell chronic lymphocytic leukemia with the Leu 11+ phenotype and novel function of activated natural killer cells is reported. The peripheral blood mononuclear cells of this patient showed large granular lymphocytes by May-Giemsa staining and lamellipodia by scanning electron micrography. Tests on reactivity with monoclonal antibodies showed that most cells were Leu 11+, OKT3-/Leu 1-, OKT4-, OKT8-, Leu 7-, OKM1-, and Tac-. Freshly collected cells lysed not only K562, which is highly sensitive to natural killer cells, but also Raji cells and Daudi cells, which are not. Leu 11+ cells were triggered by recombinant interleukin 2 (rIL2) to proliferate, produce gamma- interferon (gamma IFN), and show enhanced HLA-DR antigen expression, and 30% of the Leu 11+ cells became positive for IL2 receptor antigen (Tac). The spectrum of cytotoxic activity of these cells against target cells was extended by rIL2; after treatment with rIL2, the cells also lysed HeLa cells and even fresh cancer cells. This stimulation also increased the activities of acid phosphatase and tartrate-resistant acid phosphatase of the cells and resulted in the appearance of nonspecific esterase activity. The expanded cell population may represent a neoplasm, but these findings provide information on a novel differentiation stage of activated NK cells.
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Xing, Dongxia, William Decker, Sufang Li, Simon Robinson, Nina Shah, Hong Yang, Richard E. Champlin et al. „Targeting Chronic Lymphocytic Leukemia with Cord Blood NK Cells In NSG Model“. Blood 116, Nr. 21 (19.11.2010): 2453. http://dx.doi.org/10.1182/blood.v116.21.2453.2453.
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Abstract Abstract 2453 The incompatibility between donor killer cell immunoglobulin-like receptors (KIRs) and their corresponding ligands has been reported to reduce the risk of relapse after haploidentical and human leukocyte antigen (HLA) mismatched hematopoietic stem cell transplantation in patients with acute myeloid leukemia. We tested this KIR-ligand mismatch hypothesis in the context of allogeneic cord blood NK cells as an adoptive transfer of lymphocytes treating residual chronic lymphocytic leukemia (CLL). As a model for targeting malignant B cells in CLL, we examined allogeneic cord blood NK cell function in NOD scid gamma (NSG) mice, which carry the null interleukin-2 receptor gamma chain mutation, as the mice developed leukemia. Positively selected CD56+ cord blood NK cells were expanded ex vivo with interleukin-2 for 14 days. CLL cells were established in the NSG model by infusion of CLL cells obtained from patients. The leukemia that develops in NSG mice resembles human CLL, with a proliferating CD19+CD23+CD5+ B-cell population detected in the bone marrow, spleen, lymph nodes, and peripheral blood. Subsequently, expanded cord blood NK cells (5 × 106 per mouse) were intravenously infused into NSG-CLL mice. The NK cells that were infused into the CLL mice were typed for HLA and KIR (four main KIRs: KIR2DL2, KIR2DL3, KIR3DL1, and KIR2DL1). The CLL patients' samples that had been used in the NSG models were genotyped for KIR ligands (HLA-C group or HLA-Bw4 group and HLA-A3). In the six pairs of cord blood NK and CLL cells typed, all were HLA mismatched. Five pairs were KIR-ligand mismatched; these mice showed robust NK cell–mediated killing of CLL cells 7 days after NK cell infusion. Of interest, although no KIR-ligand mismatch was seen between the cord blood NK cells and CLL cells in one pair, we still observed NK cell–mediated killing of CLL cells in the mice. In this instance, NK cell–mediated cell killing could have been attributed to possible lower expression of HLA ligands by leukemic cells. Overall survival was significantly improved in CLL-NSG mice that had received cord blood NK cell treatment compared with overall survival in untreated mice (Kaplan-Meier analysis, p < 0.03). These results showed that adoptive transfer of allogeneic cord blood NK cells can be effective in killing CLL, and will be explored in the clinic. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.
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Cole, Marion E., Alexander MacFarlane, Mowafaq Jillab, Mitchell R. Smith, Adam D. Cohen und Kerry Campbell. „Immune Cell Dysfunction in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)“. Blood 120, Nr. 21 (16.11.2012): 3875. http://dx.doi.org/10.1182/blood.v120.21.3875.3875.
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Abstract Abstract 3875 Introduction: Immunologic environment influences progression of lymphoid malignancies. Specifically, shifts in subsets of natural killer (NK) and T cells as well as tumor expression of inhibitory ligands may contribute to ability to evade host detection. Immune dysfunction may be particularly important in CLL/SLL, as prevalent circulating tumor cells engage in persistent, widespread interactions with immune cells; commonly-used mAb therapies (e.g. rituximab, alemtuzumab) rely upon ADCC mediated by NK cells and other innate effectors; and disease course is highly variable and not fully accounted for by tumor-intrinsic prognostic factors. Therefore, to better characterize the immune system in CLL/SLL, we prospectively assessed NK and T cell frequency, phenotype, and function in a series of CLL/SLL patients. Methods: Serial blood samples (up to 3 samples each, 3–6 months apart) were collected from 31 untreated CLL/SLL patients (median age 66) and 15 healthy age-matched controls (HC), and peripheral blood lymphocytes (PBL) analyzed directly ex vivo by multiparameter flow cytometry (160 distinct parameters evaluated, primarily on T and NK cells). NK cell-mediated natural and antibody-dependent cytotoxicity were also assessed by CD107a degranulation assay following PBL co-culture with rituximab, 721.221 EBV-transformed lymphoma cells, or both. Differences in parameters between patients and controls, or between progressors and non-progressors [categorized based on updated NCI-WG criteria (Blood 2008;111:5446)] were analyzed by Wilcoxon rank-sum test. All subjects signed IRB approved informed consent forms. Results: CLL/SLL VS. HC: CLL/SLL samples displayed a marked decrease in the ability of the cytolytic CD56dim NK cells to degranulate in response to tumor, both with or without rituximab (Table 1). CD56dim NK cells from CLL/SLL patients also displayed a more immature phenotype (↓CD57, ↓NKG2D, ↑CD27, ↓KIR) than those from HC, suggesting either a block in differentiation or elimination of the most-differentiated cells. NK cell expression of NKp44, CD69, CD62L, CD137, granzyme B, perforin, or PD-1, as well as tumor-induced NK cell production of IFNγ, did not differ. CLL/SLL patients had increased total T cells with a decreased CD4:CD8 ratio, associated with increased total number of CD8 T cells, greater activation of naive CD4 T cells and transition to a memory phenotype. Treg (CD4+CD25+FoxP3+) frequency was significantly higher in CLL/SLL patients (4.5% vs. 1.8% of CD4 T cells, p=0.005), as was PD-1 expression on both CD4 and CD8 T cells, while CD137 and ICOS expression was similar in both groups. PROGRESSORS VS. NON-PROGRESSORS: With median follow-up of 16.5 months (range 1–37), 7 of 31 patients have met criteria for progression. Compared to non-progressors, progressors showed changes in the CD56bright NK cell compartment suggestive of increased activation and accelerated differentiation, with increased expression of CD69, granzyme B, perforin, CD16, and KIR. However, no significant functional differences in NK cells, or consistent differences in T cell subsets, have been observed to date. Conclusions: CLL/SLL patients have a shift toward less mature NK cells, associated with deficits in NK cell degranulation against tumor targets, compared with healthy donors. Those CLL/SLL patients who progressed had greater CD56 bright NK cell phenotypic aberrancies than non-progressors, though these findings require confirmation with a larger cohort. Taken together, our findings support the hypothesis that immune dysfunction in CLL/SLL may be due in part to a block in NK cell differentiation or loss of more mature cells, and current studies are exploring these possibilities and potential mechanisms. Given these findings, along with the immunosuppressive changes observed in the T cell compartment (↑Tregs, ↑PD-1), these data support therapeutic strategies in CLL/SLL aimed at augmenting NK and/or T cell function. Disclosures: No relevant conflicts of interest to declare.
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Anbar, Michael, Galit Granot, Pia Raanani und Uri Rozovski. „The Anti-Leukemia Effect of Natural Killer-Derived Exosomes“. Blood 134, Supplement_1 (13.11.2019): 4652. http://dx.doi.org/10.1182/blood-2019-129986.
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Circulating NK cells are the effector arm of the innate immune system. As such, they recognize transformed cells as "non-self" and kill them. Numerous ex vivo studies have demonstrated the ability of NK cells to kill allogeneic leukemia cells. Based on these in vitro studies, several past and ongoing clinical trials have shown allogenic NK cells have a strong anti-leukemia effect. However, the use of NK cells as an "off the shelf" product is limited since they, like most cellular products, induce an allo-reactive immunogenic response which limits efficacy and increases toxicity. Exosomes are nano scaled extracellular vesicles that are released by various types of cells including NK cells. Since the exosomal cargo reflects, in part, the molecular makeup of its cell of origin, we hypothesized that NK-derived exosomes maintain the anti-leukemia effect of their cell of origin. To test this hypothesis, we exposed leukemia cells to NK-derived exosomes and tested their ability to eliminate them. As a source for NK-derived exosomes we used the NK-92MI cell line. This is a genetically altered cell line which constitutively expresses IL-2 that augments the cytotoxic activity of the cells and is routinely used in clinical trials. We cultured these cells in exosome free medium for 48 hours and extracted the exosomes by ultracentrifugation. Nanoparticle analyzing system showed that the pellet was enriched with the typical ~100nm sized vesicles and these particles were visualized by electron microscopy. Western immunoblotting confirmed that these particles express CD63, a known exosomal biomarker. Subsequently, we subjected CML K562, ALL Jurkat and AML HL-60 to NK-92MI-Exo stained with PKH-26 and showed by flow cytometry that these cells uptake the exosomes in a dose- and time- dependent manner. As controls, we used exosomes derived from the human embryonic kidney 293 (HEK-293) cell line. LDH release assay showed a marked increase in LDH activity in NK-92MI-Exo exposed leukemia cells but not in HEK-293-Exo exposed leukemia cells across all cell lines tested. Similarly, flow cytometry of leukemia cells double stained for annexin/PI showed that the rate of apoptosis was markedly increased in NK-92MI-Exo exposed leukemia cells but not in HEK-293-Exo exposed leukemia cells. Together, these assays indicate that NK-92MI-Exo are cytotoxic to various leukemia cell lines and that this effect is specific to NK-derived exosomes. Encouraged by our preliminary results, we harvested leukemia cells from 4 patients with acute myeloid leukemia (AML), 4 patients with acute lymphoblastic leukemia (ALL), 4 patients with chronic lymphocytic leukemia (CLL) and normal B-cells from healthy volunteers and exposed them to NK-92MI-Exo. Similar to the cell line results, we found a marked cytotoxic effect to NK-92MI-Exo on these leukemia cells but not on normal B-cells from healthy individuals whereas HEK-293-Exo had only a minimal or no effect on primary leukemia cells. Clonal assay on peripheral blood sample from 2 CML patients showed that the number of colony forming unit -granulocyte, erythrocyte, megakaryocyte monocyte (CFU-GEMM) is significantly reduced following exposure to NK-92MI-Exo, suggesting that these exosomes target leukemia progenitor cells. Proteomics analysis of NK-92MI-Exo revealed that similar to NK cytotoxic granules, the exosomal cargo include granozymes known to induce apoptosis of target cells but unlike NK cytotoxic granules the exosomal cargo does not include perphorines, known to perforate target cell membrane. Taken together our data suggests that NK-derived exosomes have a potent cytotoxic effect across a wide range of leukemia cells. This effect is specific to NK-exosomes. Furthermore, NK-derived exosomes preferentially kill leukemia cells but not normal cells. We also show that these exosomes are toxic to leukemia progenitor cells. Proteomics analysis suggested that NK-cytotoxic granules and exosomes use different strategies to enter target-cells. Whether NK-derived exosomes may become a-cellular therapeutic strategy to combat leukemia remains to be determined. Figure Disclosures No relevant conflicts of interest to declare.
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Benson, Don, Leslie Andritsos, Mehdi Hamadani, Thomas Lin, Joseph Flynn, Jeffrey Jones, William Blum et al. „Natural Killer Cell Immune Reconstitution Predicts Outcomes for Patients with Chronic Lymphocytic Leukemia Undergoing Allogeneic Stem Cell Transplantation“. Blood 112, Nr. 11 (16.11.2008): 3300. http://dx.doi.org/10.1182/blood.v112.11.3300.3300.
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Abstract Introduction: Chronic lymphocytic leukemia (CLL), the most common form of leukemia in the Western hemisphere, is associated with severe innate, adaptive and humoral immune dysregulation. CLL remains essentially incurable, with the potential exception of allogeneic stem cell transplantation (ASCT). Natural killer (NK) cells are CD56(+), CD3(−) large granular lymphocytes that comprise a key cellular subset of the innate immune system. Preliminary in vitro data suggest an NK cell versus CLL effect exists, similar to that observed in acute myeloid leukemia (AML) and other blood cancers. Novel immune therapies for CLL (e.g., rituximab, alemtuzumab) likely exert anti-tumor effect, in part, through NK cells, in fact. Although NK cells contribute to the graft-versus-tumor effect following ASCT for other blood cancers, little is known regarding the potential role NK cells may play in the clinical allogeneic transplant setting for CLL. Herein, we provide, to our knowledge, the first report regarding NK cell immune reconstitution following ASCT for CLL. Methods: 27 CLL patients underwent reduced intensity conditioning (RIC) with ASCT. Median age was 52 years (43–69), median number of prior therapies was 3 (2–11). 55% had chemotherapy-refractory disease, and 55% had “high-risk” cytogenetics by FISH (deletion 17p or 11q22-23 abnormality). 14 patients had sibling donors, 15 had volunteerunrelated donors. Conditioning regimens included Fludarabine/TBI/Alemtuzumab (n=8), Fludarabine/Busulfan with (n=9) or without ATG (n=6), and Fludarabine/Cyclophosphamide (n=4). GVHD prophylaxis consisted of tacrolimus/MMF (n=8) or tacrolimus/methotrexate (n=19). Patients underwent bone marrow assessment prior to day +75 following ASCT. Marrow was studied for engraftment, donor chimerism, and disease status as well as lymphoid immune reconstitution by percentage of total lymphocytes and absolute lymphocyte counts by multi-color flow cytometry. Results: NK cell immune reconstitution was predicted by disease status at transplantation. Patients in complete or partial remission at the time of ASCT had more robust NK cell recovery (mean = 45% of total lymphocytes +/− SEM 5%) as compared to patients entering transplant with refractory disease (16% +/− 1, p < 0.01). No differences were observed in CD4(+) or CD8(+) T cells and no lymphocyte subset recovery was associated with CD34(+) or CD3(+) cell dosage. Achieving complete donor chimerism by day +60 was associated with robust NK cell recovery (55% +/− 1 versus 7% +/−1, p = 0.02), recovery of CD4 and CD8 T cells was not associated with chimerism status, however. Patients who went onto exhibit a complete response to ASCT had greater early NK cell reconstitution (31% +/− 3) as compared to those who had no response (8% +/− 1, p = 0.01). No differences in T cell subsets were associated with response. Patients who ultimately achieved complete remission following transplant had a lower CLL:NK cell ratio in marrow (0.35 +/− 0.07) than those who did not (8.1 +/− 1, p = 0.01). However, differences in CLL:CD4(+) and CLL:CD8(+) T cells were not predictive of response. Trends to improvement in progression free survival and overall survival were observed for patients with NK cell reconstitution above the median for the group as compared to those below; no such trends were observed regarding T cell subsets. Greater NK cell reconstitution trended towards ultimate eradication of minimal residual disease following ASCT, but no such trends were observed for T cell subsets. Conclusions: Early NK cell recovery predicts survival following autologous and allogeneic SCT in a number of hematologic malignancies; however, little is known regarding this phenomenon in CLL. To our knowledge, these are the first findings to implicate a potentially important therapeutic role for early NK cell compartment recovery in CLL following ASCT. Further research into restoring and augmenting NK cell function following RIC/ASCT for CLL is warranted.
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Sordo-Bahamonde, Christian, Seila Lorenzo-Herrero, Ana P. González-Rodríguez, Ángel R. Payer, Esther González-García, Alejandro López-Soto und Segundo Gonzalez. „LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia“. Cancers 13, Nr. 9 (27.04.2021): 2112. http://dx.doi.org/10.3390/cancers13092112.
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The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies.
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Maharaj, Dipnarine, Gayathri Srinivasan, Maria M. Abreu, Meng-Wei Ko, Anahid Jewett und Jacqueline Gouvea. „Molecular Remission Using Low-Dose Immunotherapy with Minimal Toxicities for Poor Prognosis IGHV—Unmutated Chronic Lymphocytic Leukemia“. Cells 10, Nr. 1 (22.12.2020): 10. http://dx.doi.org/10.3390/cells10010010.
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Chronic lymphocytic leukemia (CLL) accounts for 10% of hematologic malignancies. CLL is a malignancy of CD5+ B cells and it is characterized by the accumulation of small, mature-appearing neoplastic lymphocytes in the blood, bone marrow, and secondary lymphoid tissues. In the present case, a middle-aged female patient with poor prognosis unmutated IGHV CLL achieved cytogenetic and molecular remission with minimal adverse events following six cycles of low dose recombinant human IL-2 (rIL-2) in combination with low dose targeted venetoclax. Personalized low dose rIL-2 in combination with either lenalidomide or venetoclax mediates natural killer stimulation and is an effective non-toxic immunotherapy administered in the outpatient setting for poor prognosis CLL.
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ElGamal, Dalia, Yiming Zhong, Katie Williams, Chia-Hsien Wu, Ching-Shih Chen, Rosa Lapalombella und John C. Byrd. „PKC Inhibitor AEB071 Demonstrates Pre-Clinical Activity In Chronic Lymphocytic Leukemia“. Blood 122, Nr. 21 (15.11.2013): 4187. http://dx.doi.org/10.1182/blood.v122.21.4187.4187.
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Abstract Targeting B-cell receptor (BCR) downstream pathways is of therapeutic importance in eradicating chronic lymphocytic leukemia (CLL) cells. Members of the protein kinase C (PKC) family play an important role in B-cell activation. PKC-β has recently been shown to be over-expressed in CLL and essential to CLL development in the TCL1 mouse model. Mice deficient in PKC-β exhibit a survival defect in response to BCR stimulation, correlating with an inability to induce the NF-κB-dependent anti-apoptotic proteins as Bcl-xL and A1. Moreover, PKC-β-dependent activation of NF-κB in stromal cells is pivotal for the survival of B-CLL cells in vivo; wherein PKC-β inhibition was shown to prevent microenvironment protection of CLL. Additionally, PKC-β lies downstream of PLC-γ2 where activating mutations have been noted in BTK (ibrutinib) resistant patients, which conveys a potential mechanism to target resistance related to mutations in this target protein. Therefore exploration of a PCK-β inhibitor in CLL is highly justified and innovative. Sotrastaurin (AEB071) is an orally administered potent inhibitor of classical and novel PKC isotypes; with strong and specific activity on PKC-α, PKC-β and PKC-θ and lesser activity on PKC-δ, PKC-ε, and PKC-η. Pre-clinically, AEB071 has demonstrated in vivo pre-clinical activity in activated B-cell diffuse large B-cell lymphoma (DLBCL) models and is currently being tested for efficacy in CD79b mutated DLBCL. Since PKC-β is indispensable for BCR-induced NF-κB activation and B-cell survival, herein we evaluate the impact of AEB071 on CLL cell survival as a promising therapeutic to target this pathway. Our preliminary work demonstrated that AEB071 was markedly cytotoxic to CLL cells in a dose-dependent (≤6.25uM, p<0.001) and time-dependent manner (p=0.011) as measured by MTS analysis. In a whole blood assay, AEB071 exhibits a retained selective cytotoxicity against tumor cells with a modest reduction in B-CLL cells whereas no effect on T-cells or natural killer cells was detected in CLL patient samples. Notably, upon treatment of blood from healthy subjects, AEB071 showed no toxic effects on normal B-cells, T-cells and natural killer cells. AEB071 inhibits CPG-induced survival of CLL cells in vitro (p<0.01), and effectively blocks the protection induced by soluble factors such as CD40L, IL-4, and TNF (p<0.01), which are known to reduce the spontaneous apoptosis associated with CLL cells. Similar effects were observed with stromal cell contact; wherein AEB071 showed enhanced cytotoxic potency on CLL cells under co-culture conditions with stromal cells compared to CLL alone (p<0.05). Additionally, AEB071 attenuated anti-IgM-induced survival of CLL cells with a modest induction of apoptosis (p<0.001). Furthermore, treatment of PMA- or BCR-activated CLL cells with AEB071 could effectively abrogate downstream survival pathways including ERK1/2, p38MAPK, AKT, GSK3β, and NF-κB as revealed by immunoblot analysis. Collectively, this data indicate that therapeutic strategies to inhibit PKC-β have the potential to disrupt signaling from the microenvironment that lead to in vivo CLL cell survival and potentially drug resistance. Current studies are ongoing to evaluate the in vivo tolerability and therapeutic efficacy of AEB071 in the Eμ-TCL1 transgenic mouse model of CLL. In conclusion, PKC-β represents an innovative target for CLL and therefore, future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients may be warranted. Disclosures: No relevant conflicts of interest to declare.
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Gilsanz, F., J. Serna, L. Molto und M. Alvarez-Mon. „Hemolytic anemia in chronic large granular lymphocytic leukemia of natural killer cells: cytotoxicity of natural killer cells against autologous red cells is associated with hemolysis“. Transfusion 36, Nr. 5 (Mai 1996): 463–66. http://dx.doi.org/10.1046/j.1537-2995.1996.36596338025.x.
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MacFarlane, Alexander W., Mowafaq Jillab, Mitchell R. Smith, R. Katherine Alpaugh, Marion E. Cole, Samuel Litwin, Michael M. Millenson, Tahseen I. Al-Saleem, Adam D. Cohen und Kerry S. Campbell. „Natural Killer Cell Dysfunction in Chronic Lymphocytic Leukemia Is Associated with Loss of the Mature KIR3DL1+ Subset“. Blood 124, Nr. 21 (06.12.2014): 3318. http://dx.doi.org/10.1182/blood.v124.21.3318.3318.
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Abstract Background: B-cell chronic lymphocytic leukemia (CLL) is a common blood cancer characterized by high prevalence of malignant B cells in peripheral blood. Small lymphocytic lymphoma (SLL) is considered to be a different presentation of the same disease, with the malignant B cells primarily localized in lymph nodes. Natural killer (NK) cells are innate immune effectors that can spontaneously identify and kill malignant cells, especially hematopoietic cancers. In peripheral blood of CLL patients, NK cells are chronically exposed to significant tumor burden, which is predicted to influence their phenotype and function. Effective NK cell function may be particularly beneficial in CLL patients, since commonly-used monoclonal antibody therapies (e.g. rituximab, alemtuzumab) rely at least partially on ADCC-mediated by NK cells. Methods: We performed a prospective analysis of biomarkers on fresh peripheral blood lymphocytes from 25 untreated CLL patients, 10 untreated SLL and 17 age-matched healthy controls by 10-color flow cytometry. All subjects signed IRB approved informed consent forms. Our study analyzed 180 distinct biomarker parameters, with a particular focus on NK and T cells. Differences in biomarker expression between patients with SLL, CLL, and healthy controls were compared by Wilcoxon rank-sum test. Results: Absolute numbers of NK and T cells per µl of blood were significantly higher in CLL patients, and this correlated with increased B cell numbers. As indicators of immune suppression, the frequency of regulatory T cells was significantly increased in CLL samples, as were levels of PD-1 expression on T cells and CD56dim NK cells. NK cells in CLL expressed higher levels of CD27, which is characteristic of a less mature phenotype, and CD56dim cells expressed lower levels of NKG2D. Compared to healthy controls, CLL samples displayed a marked reduction in degranulation by CD56dim NK cells in response to transformed 721.221 B cells, either with or without rituximab. CD56dim NK cells from CLL patients were also less viable under resting conditions or when challenged with target cells, especially in ADCC responses. We further observed a striking reduction in the frequency and viability of KIR3DL1+ NK cells, which progressed over time in most CLL patients. Surprisingly, CLL patients with the highest levels of PD-1 expression on NK cells possessed genes for both KIR3DL1 and its ligand, HLA-Bw4. Our findings were also clearly evident in a CLL patient compared to her healthy monozygotic twin, thereby providing compelling support for the results in the full patient cohort. The altered expression levels of nearly all of the NK cell biomarkers and degranulation were less pronounced in blood samples from SLL patients, presumably due to low tumor burden in peripheral blood. Conclusions: CLL patients have increased numbers of NK cells in peripheral blood, but these NK cells are less mature, are significantly depleted of the KIR3DL1+ subset, and have deficits in degranulation response, reduced expression of NKG2D activating receptor, increased expression of inhibitory PD-1, and enhanced susceptibility to activation-induced death when challenged with tumor targets and rituxumab. Our findings support the hypothesis that immune dysfunction in CLL may be due in part to a selective loss of mature KIR3DL1+ NK cells, possibly upon encountering overwhelming tumor burden in peripheral blood, and CLL patients may benefit from therapeutic strategies that augment NK cell function. Disclosures No relevant conflicts of interest to declare.
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Zawit, Misam, Waled Bahaj, Carmelo Gurnari und Jaroslaw Maciejewski. „Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease“. Cancers 13, Nr. 17 (01.09.2021): 4418. http://dx.doi.org/10.3390/cancers13174418.
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Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease.
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Liu, Feng-Ting, Jerome Giustiniani, Timothy Farren, Li Jia, Armand Bensussan, John G. Gribben und Samir G. Agrawal. „CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia“. Blood 115, Nr. 15 (15.04.2010): 3079–88. http://dx.doi.org/10.1182/blood-2009-08-239483.
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Abstract B-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against—mean cell viability increased from 67% to 79% (P < .001). This was associated with up-regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)–induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8+ T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets.
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Velardi, A., JT Prchal, EF Prasthofer und CE Grossi. „Expression of NK-lineage markers on peripheral blood lymphocytes with T- helper (Leu3+/T4+) phenotype in B cell chronic lymphocytic leukemia“. Blood 65, Nr. 1 (01.01.1985): 149–55. http://dx.doi.org/10.1182/blood.v65.1.149.149.
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Abstract Heterogeneity within lymphocyte subsets expressing T-helper (T4+/Leu3+) or T-suppressor (T8+/Leu2+) markers was analyzed in 38 patients with B cell chronic lymphocytic leukemia (B-CLL) and in 11 age-matched controls. Co-expression of NK-lineage markers (M1, Leu7) on Leu2+ or Leu3+ cells was investigated by two-color immunofluorescence, and the proportion of granular lymphocytes within each subset was determined by cytochemical staining for acid phosphatase. B-CLL patients and normal controls had similar absolute numbers of cells per microL with T- suppressor phenotype. However, the proportion of Leu2+ cells co- expressing the Leu7 antigen was higher in the B-CLL patients than in the control subjects (54 +/- 3% v 27 +/- 4%, P less than .0001). The absolute number per microL of cells with T-helper phenotype was somewhat decreased in B-CLL patients compared with normal subjects (649 +/- 104 v 799 +/- 33, P less than .02), with a consequent decrease of the helper/suppressor ratio. Furthermore, co-expression of the Leu7 and, more strikingly, of the M1 markers was increased significantly on Leu3+ cells from B-CLL patients compared with normal controls (11 +/- 2% v 2 +/- 0.7%, P less than .002 for Leu7 and 40 +/- 5% v 4 +/- 1%, P less than .00001 for M1). Cytochemical studies showed that a large proportion of Leu3+ cells from B-CLL patients were granular lymphocytes, as suggested by the co-expression of natural killer (NK) cell markers. The emergence of a population of Leu3+ granular lymphocytes with NK markers, which is barely detectable in normal subjects, may provide an explanation for the impairment of T cell functions repeatedly described in B-CLL.
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Velardi, A., JT Prchal, EF Prasthofer und CE Grossi. „Expression of NK-lineage markers on peripheral blood lymphocytes with T- helper (Leu3+/T4+) phenotype in B cell chronic lymphocytic leukemia“. Blood 65, Nr. 1 (01.01.1985): 149–55. http://dx.doi.org/10.1182/blood.v65.1.149.bloodjournal651149.
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Heterogeneity within lymphocyte subsets expressing T-helper (T4+/Leu3+) or T-suppressor (T8+/Leu2+) markers was analyzed in 38 patients with B cell chronic lymphocytic leukemia (B-CLL) and in 11 age-matched controls. Co-expression of NK-lineage markers (M1, Leu7) on Leu2+ or Leu3+ cells was investigated by two-color immunofluorescence, and the proportion of granular lymphocytes within each subset was determined by cytochemical staining for acid phosphatase. B-CLL patients and normal controls had similar absolute numbers of cells per microL with T- suppressor phenotype. However, the proportion of Leu2+ cells co- expressing the Leu7 antigen was higher in the B-CLL patients than in the control subjects (54 +/- 3% v 27 +/- 4%, P less than .0001). The absolute number per microL of cells with T-helper phenotype was somewhat decreased in B-CLL patients compared with normal subjects (649 +/- 104 v 799 +/- 33, P less than .02), with a consequent decrease of the helper/suppressor ratio. Furthermore, co-expression of the Leu7 and, more strikingly, of the M1 markers was increased significantly on Leu3+ cells from B-CLL patients compared with normal controls (11 +/- 2% v 2 +/- 0.7%, P less than .002 for Leu7 and 40 +/- 5% v 4 +/- 1%, P less than .00001 for M1). Cytochemical studies showed that a large proportion of Leu3+ cells from B-CLL patients were granular lymphocytes, as suggested by the co-expression of natural killer (NK) cell markers. The emergence of a population of Leu3+ granular lymphocytes with NK markers, which is barely detectable in normal subjects, may provide an explanation for the impairment of T cell functions repeatedly described in B-CLL.