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Gong, Zhiliang, Daniel Kerr, Gregory T. Tietjen, James Michael Henderson, Adrienne M. Luoma, Wei Bu, Kathleen D. Cao, et al. "Mechanism of TIM1, TIM3, and TIM4 Binding to Lipid Membranes." Biophysical Journal 110, no. 3 (February 2016): 592a. http://dx.doi.org/10.1016/j.bpj.2015.11.3159.
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Alderton, Gemma K. "TIM3 suppresses antitumour DCs." Nature Reviews Cancer 12, no. 9 (August 24, 2012): 584. http://dx.doi.org/10.1038/nrc3349.
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Buckland, Jenny. "Tim3 – tolerance's little helper!" Nature Reviews Immunology 3, no. 11 (November 2003): 844. http://dx.doi.org/10.1038/nri1235.
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Alderton, Gemma K. "TIM3 suppresses antitumour DCs." Nature Reviews Immunology 12, no. 9 (August 24, 2012): 621. http://dx.doi.org/10.1038/nri3288.
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Jayaraman, Pushpa, Isabel Sada-Ovalle, Sarah Beladi, Ana C. Anderson, Valerie Dardalhon, Chie Hotta, Vijay K. Kuchroo, and Samuel M. Behar. "Tim3 binding to galectin-9 stimulates antimicrobial immunity." Journal of Experimental Medicine 207, no. 11 (October 11, 2010): 2343–54. http://dx.doi.org/10.1084/jem.20100687.
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T cell immunoglobulin and mucin domain 3 (Tim3) is a negative regulatory molecule that inhibits effector TH1-type responses. Such inhibitory signals prevent unintended tissue inflammation, but can be detrimental if they lead to premature T cell exhaustion. Although the role of Tim3 in autoimmunity has been extensively studied, whether Tim3 regulates antimicrobial immunity has not been explored. Here, we show that Tim3 expressed on TH1 cells interacts with its ligand, galectin-9 (Gal9), which is expressed by Mycobacterium tuberculosis–infected macrophages to restrict intracellular bacterial growth. Tim3–Gal9 interaction leads to macrophage activation and stimulates bactericidal activity by inducing caspase-1–dependent IL-1β secretion. We propose that the TH1 cell surface molecule Tim3 has evolved to inhibit growth of intracellular pathogens via its ligand Gal9, which in turn inhibits expansion of effector TH1 cells to prevent further tissue inflammation.
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Fu, Rong, Shaoxue Ding, Chunyan Liu, Bingnan Liu, Hui Liu, Liu Zhaoyun, Tong Chen, Tian Zhang, Zonghong Shao, and Ting Wang. "The Role of Decreased TIM-3 Expression of Natural Killer Cells in the Immune Pathogenesis of Severe Aplastic Anemia." Blood 134, Supplement_1 (November 13, 2019): 3747. http://dx.doi.org/10.1182/blood-2019-127769.
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In this study, we intend to detect the expression of TIM3 on peripheral blood NK cells in SAA patients to reveal the further immune pathogenesis of SAA. Furthermore, we tried to further elucidate the changes of functions of TIM3+ NK and TIM3-NK cells in SAA by measuring the functional molecules and cytotoxic activity of TIM3+ NK and TIM3-NK cells. Finally, we observed the therapeutic effects of TIM3 blocker, TIM3+ NK infusion and TIM3-NK infusion on SAA mice model. 1.The TIM3 expression on NK cells in SAA untreated patients was significantly lower than that in SAA remission patients (P<0.05) and normal controls (P<0.01). 2. TIM3-NK cells expressed higher NKG2D and Granzyme B than TIM3+ NK cells in untreated SAA patients. The expression of NKG2A, CD158a and CD158b on TIM3-NK cells were lower than TIM3+ NK cells. 3. The expression of CD80 and CD86 were significantly decreased after being incubated with TIM3-NK and TIM3+NK cells in SAA, especially mDC+ TIM3-NK group, significantly lower than mDC+TIM3+NK group(P<0.01). 4. The apoptosis rate (AR) of K562 cells were significantly increased after being incubated with TIM3-NK and TIM3+ NK cells in SAA, especially K562+TIM3-NK group, significantly higher than K562+TIM3+NK groups(P<0.01). 5. There was no significant difference in the level of AKT of receptor post-signal pathway protein between TIM3-NK and TIM3+ NK cells in patients with SAA, but the level of P-AKT in TIM3-NK cells is higher than TIM3+ NK cells. 6. AA mice model was established. The TIM3 expression on peripheral blood NK cells in SAA mice was significantly lower than that in TBI mice (P<0.05) and normal controls (P<0.05). TIM3-NK cells expressed higher NKG2D than TIM3+ NK cells (P<0.05). The level of P-AKT and PI3K in TIM3-NK cells is higher than TIM3+NK cells. 7. On the 17th day of model establishment, the weight, hemogram and bone marrow cells count of AA mice were significantly lower than that of NC group (p<0.05).The weight, hemogram and bone marrow cells count of CsA treatment group, TIM3+ NK cell infusion treatment group, TIM3-NK cell infusion treatment group, CsA combined with TIM3-NK cell infusion treatment group, CsA combined with TIM3 blocker treatment group has some improvement, TIM3 blocker alone treatment of AA mice slightly increased, the effect is not significant(P>0.05), and combined with CsA has no significant synergistic effect. The therapeutic effect of TIM3-NK cell infusion group was better than that of TIM3+ NK cell infusion group. The therapeutic effect of CsA combined with TIM3-NK cell infusion group was more significant than that of CsA alone group. TIM3-NK cell infusion therapy may have some synergistic effect with CSA. Conclusions 1. In this study, we found that untreated patients with SAA had lower TIM3 expression on NK cells compared with normal controls, andwere correlated with the severity of pancytopenia of SAA. 2. We further confirmed that the expression of activation molecules on TIM3-NK cells was increased and the killing function was enhanced compared with TIM3+NK cells. In addition, TIM3-NK cells have enhanced inhibition of mDCs and K562 cells and play an immunomodulatory role in SAA. Therefore, TIM3 exerts its inhibitory effect on NK cells and participates in the immune pathogenesis of SAA. Low expression of TIM3 contributes to the enhancement of NK cell function, which in turn inhibits the immune activation state of SAA and improves the disease level. 3. The expression of TIM3 on NK cells of AA mice decreased, and the activity of TIM3-NK cells was stronger than that of TIM3+ NK cells, which was consistent with the decrease of TIM3 on NK cells of SAA patients and the strong activity of TIM3-NK cells. After TIM3-NK cell reinfusion, the general condition, blood cell count and bone marrow cell count of SAA mice were improved, and the combined treatment of CsA was more effective. It may further clarify the immune pathogenesis of SAA and provide a new treatment target to improve the efficacy of SAA treatment. Disclosures No relevant conflicts of interest to declare.
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Koguchi, Ken, David E. Anderson, Li Yang, Kevin C. O'Connor, Vijay K. Kuchroo, and David A. Hafler. "Dysregulated T cell expression of TIM3 in multiple sclerosis." Journal of Experimental Medicine 203, no. 6 (June 5, 2006): 1413–18. http://dx.doi.org/10.1084/jem.20060210.
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T cell immunoglobulin- and mucin domain–containing molecule (TIM)3 is a T helper cell (Th)1–associated cell surface molecule that regulates Th1 responses and promotes tolerance in mice, but its expression and function in human T cells is unknown. We generated 104 T cell clones from the cerebrospinal fluid (CSF) of six patients with multiple sclerosis (MS) (n = 72) and four control subjects (n = 32) and assessed their cytokine profiles and expression levels of TIM3 and related molecules. MS CSF clones secreted higher amounts of interferon (IFN)-γ than did those from control subjects, but paradoxically expressed lower levels of TIM3 and T-bet. Interleukin 12–mediated polarization of CSF clones induced substantially higher amounts of IFN-γ secretion but lower levels of TIM3 in MS clones relative to control clones, demonstrating that TIM3 expression is dysregulated in MS CSF clones. Reduced levels of TIM3 on MS CSF clones correlated with resistance to tolerance induced by costimulatory blockade. Finally, reduction of TIM3 on ex vivo CD4+ T cells using small interfering (si)RNA enhanced proliferation and IFN-γ secretion, directly demonstrating that TIM3 expression on human T cells regulates proliferation and IFN-γ secretion. Failure to up-regulate T cell expression of TIM3 in inflammatory sites may represent a novel, intrinsic defect that contributes to the pathogenesis of MS and other human autoimmune diseases.
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Roussel, Mikaël, Kieu-Suong Le, Clémence Granier, Francisco Llamas Gutierrez, Etienne Foucher, Simon Le Gallou, Céline Pangault, et al. "Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade." Blood Advances 5, no. 7 (March 31, 2021): 1816–29. http://dx.doi.org/10.1182/bloodadvances.2020003080.
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Abstract In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell–like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.
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Josuttis, Manfred. "1 Tim3, 16 24.12.2007 Christvesper." Göttinger Predigtmeditationen 62, no. 1 (October 2007): 42–47. http://dx.doi.org/10.13109/gpre.2007.62.1.42.
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Leavy, Olive. "TIM3: dual role in immunity." Nature Reviews Immunology 8, no. 1 (January 2008): 4. http://dx.doi.org/10.1038/nri2239.
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Liu, Pei, Zonghong Shao, Lijuan Li, Jinglian Tao, Huaquan Wang, and Rong Fu. "Study of TIM-3 in Pathogenesis of Myelodysplastic Syndrome." Blood 132, Supplement 1 (November 29, 2018): 4388. http://dx.doi.org/10.1182/blood-2018-99-114343.
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Abstract Objective The biological characteristics of TIM3+ stem cells were further explored from the aspects of cell morphology, cytogenetics, and animal models, providing a theoretical basis for the early identification of malignant MDS clones. Methods The subjects of the study were 44 newly diagnosed MDS patients who were admitted to the General Hospital of Tianjin Medical University from July 2016 to February 2018 and 17 normal controls. TIM3+ and TIM3-stem cells were sorted from the bone marrow of 10 unteated patients with MDS, CD34+ stem cells were sorted out from the bone marrow of four normal controls. We subjected them to Wright's staining, colony-forming unit culture, and fluorescence in situ hybridization (FISH) respectively. The TIM3+ , TIM3- stem cells, and MDSC in the bone marrow of 8 unteated patients with MDS were sorted. TIM-3 inhibitors, Gal-9 inhibitors, and both of the two inhibitors were added into the three kinds of cells separately and they were cultured in groups. We examined the apoptosis of TIM3+ stem cells and TIM3- stem cells, and then analyzed the role of TIM-3/Gal-9 pathway in TIM3+ stem cells and MDSC in patients with MDS. We sorted TIM3+ , TIM3-stem cells, and MDSC from the bone marrow of 11 untreated patients with MDS and sorted CD34+ stem cells from the bone marrow of 5 normal controls. The above cells were transplanted into 32 NCG mice. 10-12 weeks later, the differentiation of human-derived cells was detected by flow cytometry. Results The TIM3+ and TIM3- stem cells were stained by Wright's stain respectively and observed under high magnification are same. The CFU assay showed that the average number of BFU-E formed by TIM3+ stem cells, TIM3- stem cells and normal bone marrow stem cells was (6 vs 11 vs 12), and the CFU-E was (3 vs 6 vs 9), CFU-GM was (5 vs 17 vs 23). The expression of Gal-9 on MDSC was significantly higher than that of normal controls (0.62±0.64% vs 0.22±0.18%, P<0.05). The proportion of apoptotic TIM3+ stem cells in the TIM3+ stem cells mixed MDSC group was significantly lower than that in the two inhibitor groups and that of apoptotic TIM3-stem cells in TIM3- mixed MDSC group [12.59(5.12, 31.24) vs 42.54(29.41, 58.39), 65.86(24.44, 99.43), P<0.05]. In the animal transplant model of our study, the expression rate of hCD45 in TIM3+ stem cells mixed MDSC group was significantly higher than that in TIM3+ , TIM3- stem cells group and normal control CD34+ stem cells group (4.99±5.47% vs 0.65±0.22%, 1.68±2.38%, 0.55±0.40%, P<0.05). The expression rate of hCD19 in TIM3+ stem cells group was significantly lower than that in TIM3-stem cells group and normal control CD34+ stem cells group (8.68±9.34% vs 27.46±18.06%, 37.38±16.14%, P<0.01); The expression rate of hCD19 in TIM3+ stem cells mixed MDSC group was significantly lower than that in TIM3-stem cells group and normal control CD34+ stem cells group (4.76±4.78% vs 27.46±18.06%, 37.38±16.14%, P<0.05). The expression rate of hCD33 in TIM3+ stem cells group was significantly lower than that in TIM3- stem cells group (11.34±14.70 % vs 22.45±8.73%, P<0.05). The expression of hCD33 in TIM3+ stem cells mixed MDSC group was significantly lower than that in TIM3-stem cells group (5.07±5.29% vs 22.45±8.73%, P<0.05). Conclusions (1) The TIM3+ and TIM3- stem cells of MDS patients are difficult to distinguish morphologically, but the colony forming ability of the two are obviously different, and the karyotype abnormalities are also different. Therefore the TIM3+ stem cells may be the earlier karyotype anomaly "malignant" stem cells. (2) The expression rate of Gal-9 on MDSC cells in bone marrow of MDS patients was significantly increased. The apoptotic rate of TIM3+ stem cells in TIM3+ stem cells and MDSC mixed culture group was significantly lower than that of TIM3- stem cells in TIM3-stem cells and MDSC mixed culture group. Blocking the TIM-3/Gal-9 pathway can inhibit the anti-apoptotic effect of MDSC on TIM3+ stem cells, providing a new target for the clearance of malignant clones in patients with MDS. (3) The number of human-derived cells detected was the largest. And MDSC can promote the expansion of TIM3+ stem cells. Human-derived cells in the TIM3+ stem cell group and the TIM3+ stem cell and MDSC mixed group cannot undergo normal myeloid and lymphoid differentiation as well as the TIM3- stem cell group or the normal control CD34+ stem cell group. It is speculated that TIM3+ stem cells may have clonal growth, while MDSC has a promoting effect. Disclosures No relevant conflicts of interest to declare.
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Sawada, Masaaki, Kumiko Goto, Akiko Morimoto-Okazawa, Miya Haruna, Kei Yamamoto, Yoko Yamamoto, Satoshi Nakagawa, et al. "PD-1+ Tim3+ tumor-infiltrating CD8 T cells sustain the potential for IFN-γ production, but lose cytotoxic activity in ovarian cancer." International Immunology 32, no. 6 (February 3, 2020): 397–405. http://dx.doi.org/10.1093/intimm/dxaa010.
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Abstract Persistent exposure to tumor antigens results in exhausted tumor-infiltrating T cells (TILs) that express the immune checkpoint molecules, PD-1 and Tim3, and lack anti-tumor immunity. To examine the exhausted status of TILs in ovarian cancer, the potential for cytokine production, proliferation and cytotoxicity by purified PD-1+ Tim3+ CD8 TILs was assessed. The production of IFN-γ and TNF-α by PD-1+ Tim3+ CD8 TILs remained the same in an intracellular cytokine staining assay and was higher in a cytokine catch assay than that by PD-1− Tim3− and PD-1+ Tim3− CD8 TILs. %Ki67+ was higher in PD-1+ Tim3+ CD8 TILs than in PD-1− Tim3− CD8 TILs. However, patients with high PD-1+ Tim3+ CD8 TILs had a poor prognosis. The potential for cytotoxicity was then examined. %Perforin+ and %granzyme B+ were lower in PD-1+ Tim3+ CD8 TILs than in PD-1− Tim3− and PD-1+ Tim3− CD8 TILs. To observe the potential for direct cytotoxicity by T cells, a target cell line expressing membrane-bound anti-CD3scFv was newly established and a cytotoxic assay targeting these cells was performed. The cytotoxicity of PD-1+ Tim3+ CD8 TILs was significantly lower than that of PD-1− Tim3− and PD-1+ Tim3− CD8 TILs. Even though PD-1+ Tim3+ CD8 TILs in ovarian cancer showed a sustained potential for cytokine production and proliferation, cytotoxicity was markedly impaired, which may contribute to the poor prognosis of patients with ovarian cancer. Among the impaired functions of exhausted TILs, cytotoxicity may be an essential target for cancer immunotherapy.
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Morimoto, Takayuki, Tsutomu Nakazawa, Ryosuke Matsuda, Fumihiko Nishimura, Mitsutoshi Nakamura, Shuichi Yamada, Ichiro Nakagawa, Young-Soo Park, Takahiro Tsujimura, and Hiroyuki Nakase. "CRISPR-Cas9–Mediated TIM3 Knockout in Human Natural Killer Cells Enhances Growth Inhibitory Effects on Human Glioma Cells." International Journal of Molecular Sciences 22, no. 7 (March 28, 2021): 3489. http://dx.doi.org/10.3390/ijms22073489.
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Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Natural Killer (NK) cells are potent cytotoxic effector cells against tumor cells inducing GBM cells; therefore, NK cell based- immunotherapy might be a promising target in GBM. T cell immunoglobulin mucin family member 3 (TIM3), a receptor expressed on NK cells, has been suggested as a marker of dysfunctional NK cells. We established TIM3 knockout in NK cells, using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9). Electroporating of TIM3 exon 2- or exon 5-targeting guide RNA- Cas9 protein complexes (RNPs) inhibited TIM3 expression on NK cells with varying efficacy. T7 endonuclease I mutation detection assays showed that both RNPs disrupted the intended genome sites. The expression of other checkpoint receptors, i.e., programmed cell death 1 (PD1), Lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and TACTILE (CD96) were unchanged on the TIM3 knockout NK cells. Real time cell growth assays revealed that TIM3 knockout enhanced NK cell–mediated growth inhibition of GBM cells. These results demonstrated that TIM3 knockout enhanced human NK cell mediated cytotoxicity on GBM cells. Future, CRISPR-Cas9 mediated TIM3 knockout in NK cells may prove to be a promising immunotherapeutic alternative in patient with GBM.
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Fu, Rong, Lijuan Li, Jiaxin Hu, Yingshuai Wang, Jinglian Tao, Hui Liu, Zhaoyun Liu, and Wei Zhang. "Elevated TIM3 expression of T helper cells affects immune system in patients with myelodysplastic syndrome." Journal of Investigative Medicine 67, no. 8 (September 11, 2019): 1125–30. http://dx.doi.org/10.1136/jim-2019-001059.
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T cell immunoglobulin and mucin domain 3 (TIM3) expression is associated with immunosuppression and clinical outcomes in many diseases. However, the specific mechanism of TIM3 in immune system has not been clarified. In order to illustrate the mechanism of TIM3 in immune system, we analyzed the expression, function and regulation of TIM3 in T helper (Th)1 cells, Th2 cells, Th17 cells and regulatory T cells (Treg) through flow cytometry in patients with myelodysplastic syndrom (MDS). Our data showed elevated proportion of Th2 and Treg cells, while the proportion of Th1 and Th17 cells decreased in patients with MDS (p<0.05) and the expression of TIM3 increased in Th1, Th17 and Treg cells in patients with MDS when compared with expression in control patients (p<0.05). The secretion of transforming growth factor-β in TIM3+Treg cells decreased in patients with MDS. These findings suggested that TIM3 might affect immune helper systems by regulating Treg cells and related immune cells. Therefore, studying the role of the TIM3 pathway in MDS is necessary and may help to provide a new way to explore the pathogenesis and treatments of MDS.
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Li, Caixia, Xiao Yu, Caihong Gu, Chao Ma, Hong Liu, Wang Tong, Qiu Zou, Lu Ye, Xiaochen Chen, and Wu Depei. "The Expression and Mechanism of Tim3 and PD-1 in Patients with Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 4948. http://dx.doi.org/10.1182/blood.v126.23.4948.4948.
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Abstract Objective: To investigatethe expression and the role of Tim3 and PD-1 on T cells of peripheral blood in patients with acute myeloid leukemia(AML). Consistently discuss the clinical significance of Tim3 and PD-1 co-expression on these cells and the mechanism of Tim3-mediated immune escape. Methods: Collectedclinical data of 36 patients who had been diagnosed with AML by bone marrow MICM classification, and then gathered their heparin anticoagulation peripheral blood before any treatment. The heparin anticoagulation peripheral blood from 20 healthy volunteers was gathered as normal control. We used the methods of immune fluorescence labeling and flow cytometry to detect expression of Tim3 on T cells. Then detected co-expression of Tim3 and PD-1 on T cells, consistently with IFN-γ secreting level on T cells. Results: 1.The proportions of CD4+ T cells and CD8+ T cells on lymphocytes in AML patients were (15.28±10.99)% and (9.19±7.54)% respectively, which were significantly lower than the proportion of normal controls [(31.12±2.22)% and (21.59±4.22)% respectively] (P<0.05). 2.The levels of Tim3 expression on CD4+ T cells and CD8+ T cells in AML patients were (4.77±3.560)% and (5.90±4.91)% respectively, which were significantly higher than the levels of normal controls [(0.73±0.62)% and (0.96±0.54)% respectively] (P<0.05). 3.Tim3 and PD-1 were co-expression on CD4+ T cells and CD8+ T cells in AML patients. 4.The IFN-γ secreting level in Tim3+ CD8+ T cells was significantly decreased than Tim3- CD8+ T cells (P<0.05). Conclusion: 1.The high expression of Tim3 on peripheral blood T cells in AML patients mediate T cell exhaustion/dysfunction, which can be an important mechanism of immune escape in leukemia. 2.PD-1 and Tim3 co-expression On CD4+ T cells and CD8+ T cells in AML patients which were dificient in there ability to produce IFN-γ. Further investigations are needed to explore the correlation of co-expression PD1 and Tim3 with process of AML, thus probably making Tim3 become another new immunotherapy target. Disclosures No relevant conflicts of interest to declare.
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Barlow, J. L., S. H. Wong, S. J. Ballantyne, H. E. Jolin, and A. N. J. McKenzie. "Tim1 and Tim3 are not essential for experimental allergic asthma." Clinical & Experimental Allergy 41, no. 7 (April 7, 2011): 1012–21. http://dx.doi.org/10.1111/j.1365-2222.2011.03728.x.
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Zhong, Tangwu, Chuanke Zhao, Shuntao Wang, Deshuang Tao, Shuxia Ma, and Chengchao Shou. "The biologically functional identification of a novel TIM3-binding peptide P26 in vitro and in vivo." Cancer Chemotherapy and Pharmacology 86, no. 6 (October 21, 2020): 783–92. http://dx.doi.org/10.1007/s00280-020-04167-0.
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Abstract Purpose Recent studies have shown that TIM3 plays an important role in T-cell failure, which is closely related to the resistance to anti-programmed cell death protein 1 (PD-1) treatment. However, there have been no reports on the application of peptide blockers to TIM3. In this study, we endeavored to identify the in vitro and in vivo anti-tumor activities of a TIM3-targeting peptide screened from the phage peptide library. Methods Phage display peptide library technology, surface plasmon resonance, flow cytometry, and mixed lymphocyte reaction were utilized to screen and demonstrate the bioactivities of P26, a TIM3-targeting peptide. Meanwhile, tumor growth assay was performed to evaluate the anti-tumor effect of P26. Results In terms of affinity, we demonstrated that P26 specifically binds to TIM3 at the cellular and molecular levels, which therefore blocks the interaction between TIM3 and Galectin-9 (Gal-9) and competes with Gal-9 to bind TIM3. Additionally, P26 significantly increases T-cell activity and elevates IFN-γ and IL-2 levels in a dose-dependent manner. Notably, P26 also counteracts Gal-9-mediated T-cell suppression. More importantly, P26 can inhibit growth of MC38-hPD-L1 tumor in mice. Conclusions P26, as a novel TIM3-binding peptide, has the ideal bioactivity connecting to TIM3 and the potential prospect of application in immunotherapy as an alternative or adjuvant to existing agents.
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Huang, X., T. W. Li, J. Chen, Z. Huang, S. Chen, and X. Guo. "POS0369 ELEVATED EXPRESSION OF TIM-3 ON NEUTROPHILS CORRELATES WITH DISEASE ACTIVITY AND SEVERITY OF ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 414.2–415. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3516.
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Background:Ankylosing spondylitis (AS) is a type of common, chronic inflammatory disease that compromises the axial skeleton and sacroiliac joints, causing inflammatory low back pain and progressive spinal stiffness, over time some patients develop spinal immobility and ankylosis which can lead to a decrease in quality of life. The last few decades, evidence has clearly indicated that neutrophil also plays key roles in the progression of AS. However, the immunomodulatory roles and mechanisms of neutrophils in AS are poorly understood. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) has been reported as an important regulatory molecule, expressed and regulated on different innate immune cells, plays a pivotal role in several autoimmunity diseases. Recent study indicates that Tim3 is also expressed on neutrophils. However, the frequency and roles of Tim3-expressing neutrophils in AS was not clear.Objectives:In this study, we investigated the expression of Tim3 on neutrophils in AS patients and explored the correlation between the level of Tim3-expressing neutrophils and the disease activity and severity of AS.Methods:Patients with AS were recruited from Guangdong Second Provincial General Hospital (n=62). Age/sex-matched volunteers as Healthy controls (HC) (n=39). The medical history, clinical manifestations, physical examination, laboratory measurements were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), Tim-3 on neutrophils were determined by flow cytometry. The mRNA expression of PD-1 and Tim-3 was determined by real-time PCR. The levels of Tim3-expressing neutrophils in AS patients were further analyzed for their correlation with the markers of inflammation such as ESR,CRP,WBC and neutrophil count(NE), as well as disease activity and severity of AS. The expression of Tim3 on neutrophils was monitored during the course of treatment (4 weeks).Results:The expression of Tim3 on neutrophils in patients with AS was increased compared to the HC (Figure 1A). However, significant difference was observed in the frequency of PD-1-expressing neutrophils between AS patients and HC (Figure 1B). The expression analysis of Tim-3 mRNA, but not PD-1, confirmed the results obtained from flow cytometry (Figure 1C). The level of Tim3-expressing neutrophils in patients with AS showed an positive correlation with ESR, CRP and ASAS-endorsed disease activity score (ASDAS) (Figure 1D). Moreover, the frequency of Tim3-expressing neutrophils in active patients(ASDAS≥1.3) was increased as compare with the inactive patients (ASDAS<1.3) (Figure 1E). As shown in Figure 1F, the frequency of Tim3-expressing neutrophils decreased after the treatment.Conclusion:Increased Tim-3 expression on neutrophils may be a novel indicator to assess disease activity and severity in AS, which may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive inflammatory responses in AS patients.References:[1]Han, G., Chen, G., Shen, B. & Li, Y., Tim-3: an activation marker and activation limiter of innate immune cells. FRONT IMMUNOL 4 449 (2013).[2]Vega-Carrascal, I. et al., Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung. J IMMUNOL 192 2418 (2014).Figure 1.(A,B)The expression of Tim3 and PD-1 on neutrophils in AS and HC were determined by flow cytometry.(C) The expression of Tim3 and PD-1 on neutrophils in AS and HC were determined by RT-PCR.(D)The correction between Tim3-expressing neutrophils and ESR,CRP,ASDAS.(E) The expression of Tim3 on neutrophils in active and inactive patients.(F) Influence of treatment on the frequency of Tim3-expressing neutrophils.Disclosure of Interests:None declared
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Kwong, Dora Lai Wan, Ngar-Woon Kam, Wai Chun Tse, Sing Hei Lok, George Tsao, and Victor Ho-Fun Lee. "The Tim3-galectin-9 interactions in the tumor microenvironment of nasopharyngeal cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2629. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2629.
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2629 Background: The complex cell interactions within the tumor microenvironment (TME) have become a crucial point in cancer research. Yet, the cell interactions might not only depend on the frequency of immune cells, but also on the inter-individual distances as cells might interact via soluble factors and/or cell-cell contact. Accordingly, the mapping of TME has recently gained importance. The aim of this study is to investigate the alternations between galectin-9 (G9) and its natural immunosuppressive receptor, T cell immunoglobulin and mucin domain 3 (Tim3) in nasopharyngeal cancer (NPC). Methods: Using multiplexed quantitative immunofluorescence, we measured the levels of G9 and Tim3 in 95 NPC patients cancerous and 8 normal specimens in tissue microarray format. Cell densities and cell-to-cell distances were quantified. The interaction between G9-expressing tumor cell lines and T cells were also studied. Results: G9-expressing tumor cells were detected in all NPC cases and were significantly higher than normal tissue. Elevated G9 was associated with shorter overall survival (OS: 89% vs 70.5% at 7 years, p: 0.019). Incremental percentages of Tim3+ cells were shown in top 10% cases strongly positive for G9-expressing tumor cells. The number of Tim3+ cells was calculated at 15µm intervals from the nearest G9-expressing tumor cells, of which a significant difference of Tim3+ cells was observed at the 0-15µm distance from G9-expressing cell in cancerous compared to normal tissues. Epithelial short distances were associated with a unfavourable prognosis. Observed short distance were hypothesized to represent Tim3+ cells actively interacting with G9-expressing tumor cells. Accordingly, In vitro cocultured of G9-ovexpressing NPC cell lines induced Tim3 expression on T cells which suppressed the T-cell mediate cytotoxicity on tumor cells. Conclusions: Our findings indicate a specific preexisting profile of Tim3+ and G9-expressing tumor cells and demonstrated that Tim3+ cells were mainly found intratumorally within 15µm of a NPC cell. The relevance of Tim3+ and G9+ distances reflect a potential marker of their functional interaction. Our results could have important implications for clinical therapeutic strategies. Since high G9 expression have poorer OS, they would deserve a different therapeutic strategy.[Table: see text]
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Li, Caixia, Xiaochen Chen, Caihong Gu, Tong Wang, Qiu Zou, Dan Yang, and Depei Wu. "TIM3 Dynamically Expressed on Peripheral Blood NK Cells in Acute Myeloid Leukemia Patients: The Expression Decreased When Untreated, and Restored While Disease Improved." Blood 128, no. 22 (December 2, 2016): 5243. http://dx.doi.org/10.1182/blood.v128.22.5243.5243.
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Abstract Objective: Preliminary study the expression and clinical significance of TIM3 on peripheral blood NK cells in patients with acute myeloid leukemia (AML). Methods: We investigated the expression characteristics of TIM3 on the peripheral blood NK cells of newly diagnosed AML patients and its clinical significance. Peripheral blood was obtained from 50 patients with newly diagnosed AML before intervention, with peripheral blood from 30 cases of healthy volunteers collected as normal control. Expression levels of TIM3 on the peripheral blood NK cells and subsets were assayed with flow cytometry. Then the expression of gamma interferon in Tim3+CD56+NK cells and Tim3-CD56+NK cells were analyzed by intracellular immunofluorescence labeling and flow cytometry. Results: Compared with the normal control, in the newly diagnosed AML patients, the NK cells percentage and the proportion of CD56dimNK/CD56+NK reduced, while the proportion of CD56brightNK/CD56+NK increased significantly, and the proportions of Tim3+CD56+NK/CD56+NK and Tim3+CD56dimNK/CD56dimNK decreased significantly. However, in AML patients with complete remission after chemotherapy, the proportion of peripheral blood NK cells and cell subsets recovered. Furthermore, compared with Tim3-CD56+NK cells, IFN-γsecretion level of Tim3+CD56+NK cells in the newly diagnosed AML patients is increased significantly. Conclusion: The dynamic expression of TIM3 on NK cell and its cell subsets before and after chemotherapy in AML patients suggest that Tim3 and NK cells may play an important role in the occurrence and development of AML. Disclosures No relevant conflicts of interest to declare.
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Starling, Shimona. "A mother's greatest gift is TIM3." Nature Reviews Immunology 17, no. 11 (October 16, 2017): 662. http://dx.doi.org/10.1038/nri.2017.120.
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Stenzel, P. "Prognostische Relevanz von TIM3 bei Nierenzellkarzinomen." Der Pathologe 39, no. 6 (July 18, 2018): 587–88. http://dx.doi.org/10.1007/s00292-018-0462-6.
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Ge, Rong-Ti, Lu Zeng, Li-Hua Mo, Ling-Zhi Xu, Huan-Ping Zhang, Hai-Qiong Yu, Min Zhang, Zhi-Gang Liu, Zhan-Ju Liu, and Ping-Chang Yang. "Interaction of TIM4 and TIM3 induces T helper 1 cell apoptosis." Immunologic Research 64, no. 2 (September 24, 2015): 470–75. http://dx.doi.org/10.1007/s12026-015-8702-9.
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Ogando-Rivas, Elizabeth, Changlin Yang, Paul Castillo, Anjelika Dechkovskaia, and Duane Mitchell. "IMMU-27. IMMUNE CHECKPOINT BLOCKADE OF EX VIVO EXPANDED T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY (ACT) FOR GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi124—vi125. http://dx.doi.org/10.1093/neuonc/noz175.520.
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Abstract BACKGROUND Despite aggressive treatments, GBM continues to have unacceptably high mortality rates. Immune-checkpoint blockade and ACT have shown excellent results in other solid tumors, especially in melanoma. Unfortunately, these results have not been extrapolated to GBM. We have developed a novel platform for ACT using tumor mRNA-pulsed dendritic cells(DCs) to in-vitro expand polyclonal populations of tumor-reactive T-cells. This platform has shown promising effects in preclinical brain tumor models (Flores et al OncoImmunology 2015, Wildes et al CCR 2018, Flores et al NatureComm 2018) and being evaluated in clinical trials at UF Health (NCT02465268,NCT03334305). STUDY OBJECTIVE Evaluate whether immune-checkpoint blockade during ex-vivo expansion of antigen-specific T-cells impact their use in ACT. METHODS CMVpp65 was used as model antigen for in-vitro activation of T-cells. Mature pp65 mRNA-pulsed DCs from CMV+ healthy donors were co-cultured with T-cells in IL2-containing medium for 15days. We tested four checkpoint inhibitor groups: PD1(n= 6), PDL1(n= 4), TIM3(n= 7) and PD1+TIM3(n= 6) that were compared with non-blockade group, respectively. Checkpoint blockade was performed every 3days. T-cell proliferation, immune-phenotyping, and IFN-g release were analyzed. RESULTS Cell proliferation was lower in all the blockade groups but significantly lower in the TIM3 (p= 0.03) and TIM3+PD1 (p= 0.01) blockade groups. TIM3 expression was significantly lower in the TIM3 (p= 0.006) and PD1+TIM3 blockade groups (p= 0.0001). There was a trend of reduced pp65 tetramer positive in the TIM3 and PD1+TIM3 blockade groups (PD1+TIM3 subgroup at 3mcg/mL, p= 0.02) and lower INFg release in the TIM3 and PD1+TIM3 blockade groups. CONCLUSION The exact role of checkpoints during expansion of T-cells for ACT is not well understood. In our study checkpoint blockade with PD-1 or TIM-3 alone or in combination did not enhance T-cell expansion or function, in fact, appeared to have an inhibitory effect on measured parameters. Our results suggest that TIM-3 may have an activating role in our system.
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Ogando-Rivas, Elizabeth, Paul Castillo-Caro, Noah Jones, Anjelika Dechkovskaia, Changlin Yang, and Duane Mitchell. "IMMU-29. LAG-3 COMPENSATES TIM-3 DOWN-REGULATION IN A HUMAN GLIOBLASTOMA MODEL." Neuro-Oncology 22, Supplement_2 (November 2020): ii111. http://dx.doi.org/10.1093/neuonc/noaa215.459.
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Abstract INTRODUCTION There are a few alternatives treatments beside the standard care for glioblastomas, one of them is adoptive cell therapy; our group has shown promising preliminary results with a dendritic cell-based vaccine that has being tested in first-in-human clinical trials. Checkpoint inhibitors have also shown promising results in the cancer arena, but not for brain tumors. OBJECTIVE We have assessed whether combination of checkpoint inhibition and transferred cellular therapy may enhance anti-tumor killing of adoptive T-cell therapies to improve survival in GBM patients. METHODS PBMCs were isolated from CMV+ donors, in order to generate dendritic cells and pulsed them with CMVpp65-mRNA. DCs were co-culture with T-cells for 15-days. Five groups were made (Tim3 at 300 ug/ml, PD1, Tim3, PD1+Tim3 at 10 ug/ml and PD1+Tim3 at 3 ug/ml) and their respective isotype-control groups. IL2 was added at 100UI/ml every 3 days as well as the blockade. Phenotyping was performed on Day0 and Day15th. Restimulation was made with pp65-pepmixes and UPGL a glioblastoma cell-line created by our group. Supernatant from overnight restimulation was analyzed for 10-cytokines. RESULTS PD1/Tim3 condition (3ug/ml), Lag3 expression was increased in central memory T-cells (mean 19.13% vs 30.98% p=0.02). On EM T-cells, Lag3 expression increased (57.98% vs 75.83%; p=0.03); for control vs 10ug/ml from combination checkpoint treatment group. On EMRA T-cells, the results were similar, Lag3 was upregulated in response of low-doses of double checkpoint inhibitor combination (8% vs 21% p=0.002). At increased doses (Tim3 at 300ug/ml), secretion of IFN-□ was reduced in T-cells treated with Tim3 vs relevant control. Secretion of IL-12 in treated T-cells with PD1/Tim3 was significantly increased. IL-1□ secretion was significantly lower in the PD1/Tim3 (10ug/ml) treatment-group compared with control-group (p < 0.004). CONCLUSIONS We have identified a potential activation component and dependent pathway between Tim3 and Lag3, once Tim3 and PD1 are blockade.
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Sun, Lili, Shengyi Zou, Sisi Ding, Xuan Du, Yu Shen, Cuiping Liu, Bimin Shi, and Xueguang Zhang. "Circulating T Cells Exhibit Different TIM3/Galectin-9 Expression in Patients with Obesity and Obesity-Related Diabetes." Journal of Diabetes Research 2020 (October 15, 2020): 1–10. http://dx.doi.org/10.1155/2020/2583257.
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Aims. Obesity is highly associated with type 2 diabetes mellitus (T2DM). The TIM3/galectin-9 pathway plays an important role in immune tolerance. Herein, we aimed to investigate the expression of TIM3 and galectin-9 in peripheral blood and to evaluate their clinical significance in patients with obesity and obesity-related T2DM. Methods. We performed flow cytometry on peripheral blood samples from healthy donors (HC), patients with simple obesity (OB), and patients with obesity comorbid T2DM (OD). The expression of TIM3 on CD3+, CD4+, and CD8+ T cells was determined. The level of galectin-9 in plasma was detected by ELISA. Results. We demonstrated the enhancement of TIM3 on CD3+, CD4+, and CD8+ T cells in the OB group when compared with healthy controls, while it was decreased significantly in the OD group. The TIM3+CD8+ T cells of the OB group were positively correlated with risk factors including BMI, body fat rate, and hipline. The concentration of galectin-9 of the OD group in plasma was significantly higher than that of healthy donors and the OB group. Moreover, the level of galectin-9 of the OD group was positively correlated with fasting insulin and C-peptide, which were two clinical features that represented pancreatic islet function in T2DM. Conclusions. Our results suggested that TIM3 and galectin-9 may be potential biomarkers related to the pathogenesis of obesity-related T2DM.
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Stempin, Cinthia Carolina, Romina Celeste Geysels, Sunmi Park, Luz Maria Palacios, Ximena Volpini, Claudia Cristina Motran, Eva Virginia Acosta Rodríguez, et al. "Secreted Factors by Anaplastic Thyroid Cancer Cells Induce Tumor-Promoting M2-like Macrophage Polarization through a TIM3-Dependent Mechanism." Cancers 13, no. 19 (September 26, 2021): 4821. http://dx.doi.org/10.3390/cancers13194821.
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Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis. However, the mechanisms of how TAMs promote ATC progression remain poorly characterized. Here, we demonstrated that the treatment of human monocytes (THP-1 cells) with ATC cell-derived conditioned media (CM) promoted macrophage polarization, showing high levels of M2 markers. Furthermore, we found that STAT3 was activated, and this was correlated with an increased expression and secretion of the inflammatory cytokine interleukin-6. Remarkably, the M2-like macrophages obtained revealed tumor-promoting activity. A cytokine array analysis demonstrated that M2-like macrophage-derived CM contained high levels of TIM3, which is an important immune regulatory molecule. Consistently, TIM3 expression was up-regulated in THP-1 cells cultured with ATC cell-derived CM. Moreover, TIM3 blockade significantly reversed the polarization of THP-1 cells induced by ATC cell-secreted soluble factors. We validated the clinical significance of the TIM3 in human TC by analyzing public datasets and found that the expression of TIM3 and its ligand galectin 9 was significantly higher in human TC tissue samples than in normal thyroid tissues. Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC.
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Barresi, Vincenza, Salvatore Napoli, Giorgia Spampinato, Daniele Filippo Condorelli, and Salvatore Santo Signorelli. "Dectin-1 and TIM3 Expression in Deep Vein Thrombosis of Lower Limbs (DVTLL)." Journal of Clinical Medicine 9, no. 11 (October 28, 2020): 3466. http://dx.doi.org/10.3390/jcm9113466.
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The pathophysiological mechanisms of venous thromboembolism are venous stasis, endothelial damage, and hypercoagulability, while less attention has been given to the role of both innate and native immunity. In this paper, we investigate the involvement of the activated immune system detected through some indicators such as TIM3 and Dectin-1 expressed by T lymphocytes. TIM3 and Dectin-1, two surface molecules that regulate the fine-tuning of innate and adaptive immune responses, were evaluated in patients affected by deep vein thrombosis of lower limbs (DVTLL). CD3+, CD4+ and CD8+ T lymphocytes obtained from patients affected by DVTLL were analysed using fluorescence-conjugated antibodies for TIM3 and Dectin-1 by an imaging flow cytometer. DVTLL patients showed a higher number of CD4+ and CD8+ T lymphocytes. TIM3 expression in T lymphocytes was very low in both DVTLL patients and controls. On the contrary, an increase in Dectin-1+ cells among CD4+ and CD8+ T lymphocytes from DVTLL patients was observed. Dectin-1 is known to play a role in inflammation and immunity and our result suggests its potential involvement in thrombotic venous disease.
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Popp, Felix, Ingracia Capino, Joana Bartels, Alexander Damanakis, Jiahui Li, Rabi Datta, Heike Löser, et al. "Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma." Cancers 13, no. 11 (May 29, 2021): 2689. http://dx.doi.org/10.3390/cancers13112689.
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Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.
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Huang, X., T. Li, J. Chen, Y. Wang, S. Chen, W. Deng, and Q. Huang. "AB0693 TIM-3-EXPRESSING NEUTROPHILS AS A NOVEL INDICATOR TO ASSESS DISEASE ACTIVITY AND SEVERITY IN ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1641.1–1642. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5466.
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Background:Ankylosing spondylitis (AS) is a type of chronic inflammatory disease that compromises the axial skeleton and sacroiliac joints. Many studies have shown that neutrophils play an important roles in the inflammatory process of AS. However, the immunomodulatory roles and mechanisms of neutrophils in AS are poorly understood. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) has been reported as an important regulatory molecule, expressed and regulated on different innate immune cells, plays a pivotal role in several autoimmunity diseases. Recent study indicates that Tim3 is also expressed on neutrophils. However, the frequency and roles of Tim3-expressing neutrophils in AS was not clear.Objectives:In this study, we investigated the expression of Tim3 on neutrophils in AS patients and analyzed the correlation between the level of Tim3-expressing neutrophils and the disease activity of AS.Methods:AS Patients were recruited from Guangdong Second Provincial General Hospital (n=49). Age/sex-matched volunteers as Healthy controls (HC) (n=39). The medical history, clinical manifestations, physical examination, laboratory measurements were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), Tim-3 on neutrophils were determined by flow cytometry. The frequencies of Tim3-expressing neutrophils in AS patients were further analyzed for their correlation with markers of inflammation ESR and CRP, disease activity and severity of AS.Results:The expression of Tim3 on neutrophils in patients with AS was increased compared to the HC (Figure 1A). The frequency of Tim3-expressing neutrophils in patients with AS showed an positive correlation with ESR, CRP and ASAS-endorsed disease activity score (ASDAS) (Figure 1B). Moreover, the frequency of Tim3-expressing neutrophils in active patients(ASDAS≥1.3) was increased as compare with the inactive patients (ASDAS<1.3) (Figure 1C).Conclusion:Increased Tim-3 expression on neutrophils may be a novel indicator to assess disease activity and severity in AS, which may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive inflammatory responses in AS patients.References:[1]Han, G., Chen, G., Shen, B. & Li, Y., Tim-3: an activation marker and activation limiter of innate immune cells.FRONT IMMUNOL4449 (2013).[2]Vega-Carrascal, I.et al., Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung.J IMMUNOL1922418 (2014).Figure 1.(A)The expression of Tim3 on neutrophils in AS and HC.(B)The correction between Tim3-expressing neutrophils and ESR,CRP,ASDAS.(C) The expression of Tim3 on neutrophils in active and inactive patients.Disclosure of Interests:None declared
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Cho, Josalyn L., Marly I. Roche, Barry Sandall, Abraham L. Brass, Brian Seed, Ramnik J. Xavier, and Benjamin D. Medoff. "Enhanced Tim3 Activity Improves Survival after Influenza Infection." Journal of Immunology 189, no. 6 (August 8, 2012): 2879–89. http://dx.doi.org/10.4049/jimmunol.1102483.
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Ngiow, Shin Foong, Michele W. L. Teng, and Mark J. Smyth. "Prospects for TIM3-Targeted Antitumor Immunotherapy: Figure 1." Cancer Research 71, no. 21 (October 18, 2011): 6567–71. http://dx.doi.org/10.1158/0008-5472.can-11-1487.
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Roth, Christine G., Kelly Garner, Stephen Ten Eyck, Michael Boyiadzis, Lawrence P. Kane, and Fiona E. Craig. "TIM3 expression by leukemic and non-leukemic myeloblasts." Cytometry Part B: Clinical Cytometry 84B, no. 3 (March 29, 2013): 167–72. http://dx.doi.org/10.1002/cyto.b.21080.
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Wolf, Yochai, Ana C. Anderson, and Vijay K. Kuchroo. "TIM3 comes of age as an inhibitory receptor." Nature Reviews Immunology 20, no. 3 (November 1, 2019): 173–85. http://dx.doi.org/10.1038/s41577-019-0224-6.
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McDonald, George B., Laura Tabellini, Barry E. Storer, Richard L. Lawler, Paul J. Martin, and John A. Hansen. "Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment." Blood 126, no. 1 (July 2, 2015): 113–20. http://dx.doi.org/10.1182/blood-2015-03-636753.
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Key Points Before GVHD treatment, informative plasma biomarkers included TIM3, IL6, sTNFR1 (for grade 3-4 GVHD), and ST2 and sTNFR1 (for NRM at 1 year). In a day 14 landmark analysis, plasma TIM3 was predictive of grade 3-4 GVHD.
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Anagnostou, Theodora, Zhi-Zhang Yang, Hyojin Kim, Shahrzad Jalali, Jose C. Villasboas, Hongyan Wu, Tammy Price-Troska, Anne J. Novak, and Stephen M. Ansell. "Immune Phenotyping of Cytotoxic T-Cells Reveals a Novel Population of TIM3 Expressing Cells That Lack PD1 and Are Associated with Good Outcomes in Marginal Zone Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 2790. http://dx.doi.org/10.1182/blood-2019-127757.
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The outcomes of lymphoma patients treated with PD1 inhibitors (PD1i) vary significantly across different histologies with objective responses rates that are around 70% in classical Hodgkin lymphoma, but significantly lower, around 10%, in indolent non-Hodgkin lymphomas (iNHL). This may be due in part to the inability of PD1i to restore the function of exhausted T-cells (Tex) in the tumor microenvironment (TME). PD1 is expressed on various T-cell subsets, including effector cells and Tex. In this study we sought to identify markers of exhaustion beyond PD1 that define T-cell subsets with high reactivation potential in marginal zone lymphoma (MZL). To define different stages of exhaustion in MZL, we developed and validated a mass cytometry (CyTOF) panel which integrates T-cell markers of lineage, differentiation, activation, suppression, cytokine production and transcription factors associated with exhaustion. We analyzed 35 MZL spleens obtained at diagnosis and 6 reactive spleens. We identified a population of CD8 cells in MZL that express TIM3 without PD1, compose 1.5% (range 0.14-4.88%) of total CD8 cells and expand with activation through the TCR (6.2% of CD8, range 0.6-14.2%). Prolonged cytokine exposure has been shown to induce exhaustion in healthy T-cells, and so to determine whether PD1-TIM3+ cells are Tex, we treated healthy donor T-cells with activating beads and IL12 and analyzed them by flow cytometry. We showed that PD1-TIM3+ cells expand with repetitive activation and IL12 treatment suggesting that they are Tex. Since Tex have been shown to have a distinct transcription profile compared to functional effector T-cells, we analyzed the expression of several transcription factors (TFs) that are upregulated in Tex by CyTOF and compared them to other subsets of T-cells. PD1-TIM3+ cells expressed higher levels of Eomes, Tbet, TOX and Helios compared to activated effector cells, confirming that they are Tex, but lower levels levels of the same TFs compared to PD1+TIM3+ cells, consistent with a less severely exhausted phenotype. To characterize the function of PD1-TIM3+ cells, we manually gated on subsets of CD8+ non-naïve cells that were stained with the CyTOF panel and compared the different subsets. We showed that PD1-TIM3+ cells arise from effector cells, maintain their polyfunctionality by producing cytokines and chemokines and have a unique cytokine production profile, including perforin, granzyme B and proinflammatory cytokines, such as IL17A. Importantly, PD1-TIM3+ cells produced higher levels of most cytokines compared to more severely Tex expressing both PD1 and TIM3 (Fig 1). We then performed tSNE analysis where similar objects are modeled by nearby points. We determined that PD1-TIM3+ cells cluster together, suggesting that they are phenotypically homogeneous cells in terms of function and expression of activation markers and are significantly different from PD1+TIM3+ cells (Fig 2). We finally blocked PD1 or TIM3 and analyzed the effect of each antibody blockade on function. We showed that TIM3 blockade was able to restore the production of most cytokines to higher degrees than PD1 blockade. In addition, TIM3 blockade led to upregulation of CD28, which is critical for the rescue of Tex through costimulation, while PD1 blockade did not. We then analyzed the clinical outcomes of all 34 MZL patients. The frequency of PD1-TIM3+ cells was lower among observed patients who failed to achieve an event-free survival (EFS) of 12 months (EFS12) (0.8% vs 1.7%, p=0.02) and among treated patients that failed an EFS of 24 months (EFS24) (0.9 vs 1.7%, p=0.03), when compared to patients that reached these endpoints. Higher levels of PD1-TIM3+ cells were also associated with a trend towards improved overall survival (OS). Five-year OS was 88% vs. 69% in patients with PD1-TIM3+ levels >2% and <2% of total CD8 cells respectively (p=0.1) (Fig 3). Our study provides insights into the mechanisms of failure of PD1i in MZL and identifies a novel population of Tex with high reactivation potential which is clinically relevant and could serve as a target for future immunotherapies in iNHL. Disclosures Anagnostou: American Society of Hematology, Mayo Clinic/Iowa Lymphoma SPORE, Mayo Clinic Immune Monitoring Core, Mayo Clinic Hematology Small Grant: Research Funding. Novak:Celgene Coorperation: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding.
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Schroll, Andrea, Kathrin Eller, Julia M. Huber, Igor M. Theurl, Anna M. Wolf, Günter Weiss, and Alexander R. Rosenkranz. "Tim3 Is Upregulated and Protective in Nephrotoxic Serum Nephritis." American Journal of Pathology 176, no. 4 (April 2010): 1716–24. http://dx.doi.org/10.2353/ajpath.2010.090859.
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Huang, C., C. Xia, H. Zhu, J. Wo, F. Chen, M. Zheng, and Z. Chen. "Association of PD1 and TIM3 polymorphisms with HBV susceptibility." Journal of Hepatology 68 (April 2018): S802. http://dx.doi.org/10.1016/s0168-8278(18)31877-4.
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Jayaraman, Pushpa, Miye K. Jacques, Chen Zhu, Katherine M. Steblenko, Britni L. Stowell, Asaf Madi, Ana C. Anderson, Vijay K. Kuchroo, and Samuel M. Behar. "TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection." PLOS Pathogens 12, no. 3 (March 11, 2016): e1005490. http://dx.doi.org/10.1371/journal.ppat.1005490.
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Rivalland, Gareth, Marzena Walkiewicz, Gavin Michael Wright, and Thomas John. "Small cell lung cancer: The immune microenvironment and prognostic impact of checkpoint expression." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 8569. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8569.
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8569 Background: To date, immunotherapy has had limited success in small cell lung cancer (SCLC), despite the tumor’s high mutation load. Little is understood of the immune tumor microenvironment in SCLC due to a paucity of resected tumor. We present a SCLC cohort and describe the prognostic impact of checkpoint expression. Methods: SCLC tissue microarrays with triplicate cores from 105 SCLC specimens underwent IHC assessment for PD-L1, PD-L2, LAG3, TIM3, FoxP3, CD4 and CD8 on tumor and/or tumor infiltrating lymphocytes (TILs). Checkpoint positivity was defined > 5% tumor expression or TIL expression in > 5% of the total core area. Associations with clinicopathologic characteristics and survival were assessed. A Cox model was used for univariate and multivariate survival analysis. Results: Tumor expression of PD-L1 was positive (+) in 17/95 (18%), PD-L2+ in 2/96 (2%), and TIM3+ or LAG3+ in no cases. TILs expressed PD-L1+ in 64/95 (67%), PD-L2+ in 22/96 (22%), TIM3+ in 57/96 (59%) and LAG3+ in 43/96 (45%). FoxP3+ lymphocytes were found in all samples (range 0.02 – 2.98% of total core). TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all significantly correlated (p value ≤0.001 for all comparisons), and were associated with high FoxP3+ expression. All four checkpoints were expressed on TILs in 20/105 (19%) patients. PD-L1+ and PD-L2+, but not TIM3 or LAG3, on TILs were significantly higher in limited stage compared with extensive stage SCLC (76% v 52%, p 0.045 and 28% v 7%, p 0.02 respectively). There was no association between stage and tumor expression. TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all associated with improved prognosis. PD-L1+ median OS: 17.2 v 7.9 months (HR 0.36; 95%CI 0.22 – 0.6; p < 0.001). Univariate analysis showed stage and TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were associated with improved survival, but only stage and PD-L1+ TILs remained significant on multivariate analysis (p < 0.01). Conclusions: Immune checkpoint molecules are frequently expressed in SCLC-associated TILs, but not the tumor itself. TIL expression of checkpoint molecules is associated with improved survival. Limited tumor expression of PD-L1 and an exhausted immune cell phenotype may contribute to immunotherapy failure.
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Pignon, Jean-Christophe, Opeyemi Jegede, Christine Horak, Megan Wind-Rotolo, Paul J. Catalano, Jonian Grosha, Abdallah Flaifel, et al. "Evaluation of predictive biomarkers for nivolumab in metastatic clear cell renal cell carcinoma (mccRCC) using RECIST and immune-related (IR) RECIST." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 619. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.619.
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619 Background: Development of predictive biomarkers would help select patients more likely to respond to nivolumab (nivo) in mccRCC. Here we evaluated biomarkers for nivo using endpoints based on either RECIST 1.1 (ORR and PFS) or irRECIST (irORR and irPFS), which were proposed to more accurately predict benefit of immunotherapy. Methods: We retrospectively analyzed tumor tissues from the Checkmate 010 trial (PMID: 25452452). PD-L1 expression on tumor cells (TC) was studied by IHC. Percentages of CD8+ tumor infiltrating cells (TIC) expressing the immune checkpoints PD1, TIM3 and LAG3 (either alone or in various combination) were determined by immunofluorescence (IF) and their predictive value assessed by the presence of a dose response relationship (DRR) with PFS or irPFS. The candidate biomarkers were then correlated with clinical outcomes using optimized cutoffs. Results: As previously shown, TC PD-L1 expression was not associated with PFS or ORR. In contrast, pts with TC PD-L1 ≥1% had longer median irPFS and higher irORR (Table). None of the TIC phenotypes determined by IF displayed a DRR with PFS. Conversely, we found that % of CD8+ TIC that are PD1+TIM3-LAG3- (% CD8+ PD1+TIM3-LAG3- TIC) was correlated with irPFS (HR = 0.58, p = 0.007). At the optimized cutoff (36%), pts with high % CD8+ PD1+TIM3-LAG3- TIC had longer median irPFS and higher irORR (Table). Notably, combination of TC PD-L1 expression with % CD8+ PD1+TIM3-LAG3- TIC identified 3 groups of pts for which irPFS and irORR were significantly different (Table). Conclusions: Our results suggest that, in mccRCC, tumor-immune biomarkers for nivo response show improved association with clinical endpoints defined by irRECIST relative to RECIST. The increased predictive value of TC PD-L1 combined with immune checkpoints expression on CD8+ TIC seen in this cohort requires independent validation. [Table: see text]
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Petersen, Christopher Thomas, Neera Jagirdar, and Edmund K. Waller. "Oligoclonal T cells transiently expand and express TIM3 and LAG3 following CD19 CAR t cell therapy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e19017-e19017. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e19017.
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e19017 Background: CAR T therapies targeted towards the CD19 antigen have shown tremendous promise in the treatment of multiple B cell malignancies. However, not all B cell malignancies show the same degree of response; B cell lymphomas such as DLBCL have been more resistant to CAR T-mediated lysis. The reasons for the higher treatment failures and relapse rates in this setting are poorly understood which prompts investigation into the dynamics of T cell responses following CAR T infusion. Methods: Peripheral blood was collected from a single DLBCL patient enrolled on a single-patient compassion-use CAR T cell protocol utilizing a single chain CD19 with 4-1BB co-stimulatory signaling domain (NCT02445248 IND 16130). Blood samples were obtained prior to and on day 1, 8, 17, 24, 31, and 58 post-CAR T infusion. A bone marrow aspirate was collected on day 58. Mononuclear cells were collected by ficoll gradient and cryopreserved. Flow cytometry was performed on thawed samples to identify CAR T cells and surface markers. TCR sequencing was performed using the ImmunoSeq platform on an additional sample from each time point. Results: TCR sequencing revealed distinct waves of oligoclonal T cells within the first two months following CAR T therapy. A population of T cells expressing Vβ 20 appeared early following CAR T infusion and contracted by day 17. Additionally, a population of cells expressing Vβ 27.1 also expanded at the peak of the response (D8), but remained at a high frequency up to two months post-treatment. A third wave of T cells expressing Vβ 7.3 expanded in the blood and marrow on day 58. The expression of TIM3 and LAG3 also changed over time. TIM3 was expressed predominantly in the CD8 compartment while LAG3 expression was limited to the CD4 compartment. Expression of both increased at peak and decreased over time. Low levels of PD-1 expression were detected in contrast to the much higher levels of TIM3. Conclusions: The waves of oligoclonal T cell expansion and dynamic expression of TIM3 and LAG3 provide further insight into the CAR T response and may provide new possible targets for supportive therapies that can enhance the overall response. Clinical trial information: NCT02445248.
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Friedlaender, Alex, Alfredo Addeo, and Giuseppe Banna. "New emerging targets in cancer immunotherapy: the role of TIM3." ESMO Open 4, Suppl 3 (June 2019): e000497. http://dx.doi.org/10.1136/esmoopen-2019-000497.
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Currently, the programmed death-1/programmed death ligand-1 and the cytotoxic T-lymphocyte-associated protein 4 are the two commonly targeted immune-checkpoint inhibition pathways. These drugs have significantly improved the prognosis of many cancer types. While immune-checkpoint inhibitors have revolutionised the treatment of many cancer types, the majority of patients still progress. Several treatment strategies have been pursued to improve current results. One approach is to combine two checkpoint inhibitors, currently with promising results in melanoma, renal cell carcinoma and a subset of non-small-cell lung cancer patients. The identification of new checkpoint targets could allow the field of immuno-oncology to evolve further. We will discuss one of the most promising immune-checkpoint targets currently under investigation, the T-cell immunoglobulin and mucin domain-3.
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LeGrand, Jason N., Stephanie C. Heidemann, C. Scott Swindle, and Christopher A. Klug. "Identification of Cytogenetically Normal Human CD34+CD38+ Hematopoietic Stem/Progenitor Cells from Inv(16)+ Leukemic Bone Marrow." Blood 124, no. 21 (December 6, 2014): 1059. http://dx.doi.org/10.1182/blood.v124.21.1059.1059.
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Abstract For many subtypes of AML including cases with the inv(16), mutations that give rise to the leukemic phenotype occur, at least in part, in the hematopoietic stem/progenitor (HSPC) cell subset, as suggested by studies showing that primitive CD34+ CD38- bone marrow cells can function as leukemia-initiating cells (LIC) when transferred into immunodeficient mice. A significant challenge has been that LIC share many of the same cell-surface markers as their normal HSPC counterparts, thus making it difficult to purify and functionally characterize either subset from the bulk bone marrow of leukemia patients. Here we report the FACS analysis of several previously reported human LIC markers on bone marrow samples from inv(16) AML patients and show that a combination of TIM3, CLL1, and CD33 can significantly enrich for a rare population of CD34+ CD38- cells that lack the inv(16) fusion mRNA when tested by nested RT-PCR. Heterogeneous expression of these markers among different patient samples often causes incomplete elimination of the fusion mRNA when FACS-sorting the CD34+ CD38- population as single TIM3-, CLL1-, or CD33- subsets. The combination of TIM3 with CLL1 and/or CD33 leads to a more consistent elimination of the fusion mRNA from the FACS-sorted CD34+ CD38- subsets. Results from methylcellulose assays showed that the TIM3- CLL1- CD33- subset of CD34+CD38- cells could form multiple colony types, including CFU-GEMM, that were all negative for the fusion mRNA by RT-PCR. In contrast, colonies derived from bulk bone marrow were all positive for the fusion mRNA. The TIM3- CLL1- CD33- subset of CD34+CD38- cells displayed greater than 600-fold enrichment for progenitor activity compared to bulk bone marrow but did not form additional colonies upon serial re-plating. These results have important implications for the therapeutic targeting of inv(16)+ hematopoietic stem/progenitor cells in patients with relapsed and refractory disease and for purification of normal HSPC from leukemic bone marrow samples. Disclosures No relevant conflicts of interest to declare.
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Kumar, Jitendra, Ritesh Kumar, Amir Kumar Singh, Elviche L. Tsakem, Mahesh Kathania, Matthew J. Riese, Arianne L. Theiss, Marco L. Davila, and K. Venuprasad. "Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function." Journal for ImmunoTherapy of Cancer 9, no. 1 (January 2021): e001688. http://dx.doi.org/10.1136/jitc-2020-001688.
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BackgroundChimeric antigen receptor (CAR) T-cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid tumors. This is partly because the CAR T cells become dysfunctional and exhausted in the tumor microenvironment. However, the key pathways responsible for impaired function of exhausted cells remain unclear, which is essential to overcome CAR T-cell exhaustion.MethodsAnalysis of RNA-sequencing data from CD8+ tumor-infiltrating lymphocytes (TILs) led to identification of Cbl-b as a potential target. The sequencing data were validated using a syngeneic MC38 colon cancer model. To analyze the in vivo role of Cbl-b in T-cell exhaustion, tumor growth, % PD1+Tim3+ cells, and expression of effector cytokines were analyzed in cbl-b+/+ and cbl-b–/– mice. To evaluate the therapeutic potential of Cbl-b depletion, we generated a new CAR construct, hCEAscFv-CD28-CD3ζ.GFP, that recognizes human carcinoembryonic antigen (CEA). cbl-b+/+ and cbl-b–/– CEA-CAR T cells were generated by retroviral transduction. Rag–/– mice bearing MC38-CEA cells were injected with cbl-b+/+ and cbl-b–/–; CEA-CAR T cells, tumor growth, % PD1+Tim3+ cells and expression of effector cytokines were analyzed.ResultsOur results show that the E3 ubiquitin ligase Cbl-b is upregulated in exhausted (PD1+Tim3+) CD8+ TILs. CRISPR-Cas9-mediated inhibition of Cbl-b restores the effector function of exhausted CD8+ TILs. Importantly, the reduced growth of syngeneic MC38 tumors in cbl-b–/– mice was associated with a marked reduction of PD1+Tim3+ CD8+ TILs. Depletion of Cbl-b inhibited CAR T-cell exhaustion, resulting in reduced MC38-CEA tumor growth, reduced PD1+Tim3+ cells and increased expression of interferon gamma, tumor necrosis factor alpha, and increased tumor cell killing.ConclusionOur studies demonstrate that deficiency of Cbl-b overcomes endogenous CD8+ T-cell exhaustion, and deletion of Cbl-b in CAR T cells renders them resistant to exhaustion. Our results could facilitate the development of efficient CAR T-cell therapy for solid tumors by targeting Cbl-b.
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el Halabi, Layal, Julien Adam, Virginie Marty, Jacques Bosq, Julien Lazarovici, Alina Danu, Vincent Ribrag, and David Ghez. "Strong Expression of the Immune Checkpoint Regulators LAG3 and Tim3 in Hodgkin Lymphoma." Blood 128, no. 22 (December 2, 2016): 2952. http://dx.doi.org/10.1182/blood.v128.22.2952.2952.
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Abstract Background: Recent results of immune checkpoint blockade trials have provided a proof of concept for immunotherapy in classical Hodgkin lymphoma (cHL) with more than two third of relapsed/refractory patients responding to blockade of the PD1/PDL1 axis. Unfortunately, there is still a proportion of patients who will present primary or secondary resistance to immunotherapy. Besides the PD1/PDL1 axis, several other molecules are critical regulators of the immune response and may be the target of therapeutic intervention. Combined immune checkpoint targeting has shown interesting results in preclinical and clinical trials in several types of tumors. Methods: Patients with initially diagnosed or relapsed cHL for whom formalin fixed paraffin embedded (FFPE) tissue was available at our institution were identified. Fifty-seven cases were selected depending solely on the availability and the quality of the FFPE blocks. Expression of the following immune checkpoints PD1, PDL1, LAG3, TIM3 was assessed using immunohistochemical methods with a threshold of 5% set for positivity. Results: Complete results for 25 cases were available at the time the abstract was written. Hodgkin and Reed Sternberg cells (HRS) were identified morphologically upon microscopic examination. Consistently with data published in the literature, HRS stained positively and intensely for PDL1 in 100% of the cases (25/25). HRS were positive for Tim3 in 36% (9/25) of cases but with more varying intensities. No PD1 or LAG3 expression was found on HRS cells except for a single case where 5% of HRS stained weakly for LAG3. In the tumor microenvironment, PD1 expression was detected in 65% of cases (15/23) and PDL1 in 60% of cases (15/25). Impressively, LAG3 and TIM3 stained positively in 96% (23/24) and 92% (24/25) of cases respectively. Lymphocyte-rosetting was present in 9/25 cases. These CD4+ FoxP3- T cells surrounding HRS were positive for PD1 in 5 cases, for LAG3 in 2 cases and for both PD1 and LAG3 in 2 cases, suggesting they represented exhausted T-cells. Concomitant expression of PD1 and PDL1 in the tumor microenvironment was present in 43% of cases (10/23). Conclusion: LAG3 and TIM3 are nearly universally expressed in the tumor microenvironment of cHL. These findings provide a strong rationale for their blockade alone or in combination in relapsed/refractory patients with cHL. The role of TIM3 expression by HRS remains unclear. Correlation of these findings with clinical data and survival outcome of the patients will be done for the whole sample. Disclosures Ribrag: NanoString: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.
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Tcvetkov, Nikolai Yu, Elena V. Morozova, Olga S. Epifanovskaya, Elena V. Babenko, Maria V. Barabanshikova, Kirill V. Lepik, Eugene A. Bakin, et al. "Profile of Checkpoint Molecules Expression on Bone Marrow Cell Populations in Patients with High-Risk Myelodysplastic Syndrome." Blood 136, Supplement 1 (November 5, 2020): 43–44. http://dx.doi.org/10.1182/blood-2020-141997.
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Background Immune checkpoint (IC) inhibitors (ICI) is a promising group of agents with potential effect in myelodysplastic syndrome (MDS). However, there is not enough data on the pattern of IC expression in MDS bone marrow, though this can guide future therapies with ICI. Methods We prospectively included 57 patients with high risk MDS during 2019-2020 years after signing informed consent for participation in research. We used 7 eight-colored panels in each patient to define IC expression on T- and NK-cells (CD3, CD8, CD4, CD56, CD16), myeloid precursors (CD117, CD34), T-regulators (CD25, CD4), myeloid-derived suppressor cells (CD15, CD11b, CD14, HLA-DR, CD33). In each population we assessed expression of CD279, CD152, CD223, TIM3, CD273, CD274, CD275, CD80. Results In lymphoid populations we observed an extremely high percentage of PD-1 positive lymphocytes (10.5 ± 8.0% of all nucleated cells), including PD-1 positive CD4 lymphocytes (6.3 ± 3.7%) and CD8 lymphocytes (4.7 ± 3.5%). Interestingly, on average 63 ± 34% of all lymphocytes were PD-1 positive (Figure 1A), which indicates an extreme degree of T-cell exhaustion and significant exploitation of the PD-1 system by a malignant tumor. Among the PD-1 ligands PD-1L predominated, however it was present only on a small percentage of myeloid precursors (2.2 ± 0.39% of nucleated cells), but most of the PD-1L ligand expression was observed on granulocytes in the process of their differentiation from myeloid precursors (5.8 ± 4.1% of nucleated cells), and in some patients the proportion of such granulocytes reached more than 20%. Moreover, on the cells of the monocytic series, PD-1L is practically not expressed, but CD80 is expressed, a ligand for CTLA4 (1.6 ± 0.7% of nucleated cells). Interestingly, despite the presence of expression of CD80 on monocytic and dendritic cells, the receptor for this ligand on T-lymphocytes was practically absent. The proportion of such cells was only 0.02 ± 0.01%, i.e. the expression of CD80 facilitates the activation of lymphocytes through interaction with CD28 rather than the suppression of the immune response through CD152. Thus, it can be suggested that CTLA4 does not have a clinically significant role in MDS. At the same time, a certain number of TIM3 positive lymphocytes were observed, the proportion of which was 0.42 ± 0.16%, and the percentage of lymphocytes carrying this receptor was 3.6 ± 1.2% (Figure 1A). However, significantly greater TIM3 expression was detected on NK cells. The proportion of such cells was 1.3 ± 0.6% of all nucleated cells, while 30% of all NK cells carried the TIM3 receptor (Figure 1A). Only 0.1% of cells from early myeloid progenitors that expressed TIM3 receptor were detected during flow cytometry, while the proportion of TIM3 positive myeloid cells increased during maturation just in the same way as the PD-1L. Expression of Gal9 was negligible, as it is a protein secreted into the intercellular space. Only a small percentage is associated with cell membranes. The analysis of the correlation matrix showed synchronous changes in the number of most bone marrow T-cell populations. A negative correlation of the level of myeloid tumor precursors actively expressing IC ligands and activated T cells, expressing CD223, NK cells, NKT was observed. The total number of myeloid tumor precursors positively correlated with the number of PD-1 positive lymphocytes (Figure 1B). Conclusion It was found that IC system plays a role in high-risk MDS. Moreover, the expression of ligands is mainly realized during maturation of blast cells into granulocytes, which are the main population expressing these inhibitory molecules. The leading role in the suppression of the T-cell response in MDS is played by the PD-1-PD-1L system, the CTLA4 system plays a minor role in our study cohort. The second most important system is GAL9-TIM3, effecting predominantly NK cells, while T cell are less affected. Thus, the data obtained justify the trials of dual blockade with anti-PD-1 and anti-TIM3 agents in high-risk MDS. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Thapa, Bibhusal, Marzena Walkiewicz, Gareth Rivalland, Carmel Murone, Khashayar Asadi, Stephen Barnett, Simon Knight, Neil Watkins, Prudence A. Russell, and Thomas John. "Immune microenvironment in mesothelioma: Looking beyond PD-L1." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 8515. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8515.
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8515 Background: Studies using immune checkpoint inhibitors in mesothelioma (MM) have shown promise. Differences in response to PD-L1 and PD-1 inhibitors (10% vs 25%) have been reported. Also, expression of PD-L1 alone appears to be a limited predictor. As the roles of the multiple check point receptors and their ligands become defined, an understanding of their expression and interplay in the mm tumour microenvironment, which could affect suitability for checkpoint inhibition therapy, has become necessary. Methods: Tissue microarrays were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. Tumour infiltrating lymphocytes (TILs) were assessed in the stroma and expressed as a % of stromal area within invasive tumour. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. To quantify the immunosuppressive milieu, we combined our assessment of PD-L1, PD-L2 and TIM3 expression to derive an “Immune checkpoint score (ICS)” and explored its correlation with the tumour microenvironment and clinicopathological covariates. We are also exploring its predictive value in an independent cohort of mm patients who have received anti-PD-1 treatment. Results: Amongst 329 patients evaluated, PD-L1 was positive (+) in 41.7% and PD-L2+ in 24.5%. TIM3+ lymphocytes were found in 99.4% but LAG3+ lymphocytes in only 0.2%. 28/173 (16%) of PD-L1- patients were PD-L2+ and 31/136 (22%) PD-L1 and PD-L2 negative patients had high infiltration with TIM3+ lymphocytes. High ICS was associated with non-epithelioid histology, increased TILs and poorer survival. On multivariate analysis, high TILs, non-epithelioid histology and poor physiological status remained significantly associated with poorer survival. Data on the predictive role of ICS score will also be reported. Conclusions: While co-expression of PD-L1, PD-L2 and TIM3 can occur, their expression is mutually exclusive in a large proportion of patients. The expression of PD-L2 may explain differences in responses seen between PD-1 compared to PD-L1 inhibitors. A comprehensive assessment of these multiple immunosuppressive pathways may be necessary to truly gauge the immunosuppressive environment and tailor immunotherapy for individual cases.
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Griguolo, Gaia, Anna Tosi, Valentina Guarneri, Maria Vittoria Dieci, Susan Fineberg, Annavera Ventura, Luc Bauchet, et al. "Profiling of immune checkpoint biomarkers by multiplex immunofluorescence in breast cancer brain metastases." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2021. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2021.
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2021 Background: Despite potential clinical implications, the complexity of immune microenvironment in breast cancer (BC) brain metastases (BM) is still poorly understood. Multiplex immunofluorescence (mIF) allows simultaneous visualization of several IF labeled proteins while maintaining spatial information. This novel technique can be used to comprehensively describe BCBM immune microenvironment, potentially providing useful information to guide novel therapeutic approaches. Methods: Clinical data and archival BM samples from 60 BC patients undergoing neurosurgery (2003-2018) at three institutions were collected. BCBMs were characterized using a custom mIF panel, including immune checkpoint and co-inhibitory molecules (CD3, PD1, PD-L1, TIM3, LAG3, CD163) and localization (keratin for tumor recognition) markers. Mean marker density was determined by digital image analysis (positive cells/mm2) and classified in tumor and stroma areas. Associations between immune marker densities, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Sixty BCBM samples were analyzed; 32% HR+/HER2-, 38% HER2+, 30% HR-/HER2-. At a median follow-up of 43 months, the only clinical variable associated with OS was BC subtype (shortest for HR-/HER2- and longest for HER2+, p=0.02). In the total sample area and tumor area, no significant difference in marker density was observed according to BC subtype. In the stroma area, a significant difference in TIM3+ cell density was observed according to BC subtype (highest density in HR+/HER2- and lowest density in HER2+ tumors, Kruskal-Wallis p=0.017). Higher CD163 density (a marker of M2 macrophage polarization), both in the tumor and in the stroma area, was significantly associated with worse OS, even after correction by BC subtype. In the subgroup of patients with HR+/HER2- BCBM, high TIM3+ cell density in the stroma area was significantly associated with longer OS (median OS 54.1 versus 23 months respectively for TIM3+ density above and below median value; p=0.01). Conclusions: In BCBM, stromal TIM3+ immune infiltrate differs according to BC subtype. M2 macrophage polarization is consistently associated with worse OS across all BC subtypes and might represent a potential therapeutic target for these patients.[Table: see text]
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Solinas, Cinzia, Pushpamali De Silva, Dominique Bron, Karen Willard-Gallo, and Dario Sangiolo. "Significance of TIM3 expression in cancer: From biology to the clinic." Seminars in Oncology 46, no. 4-5 (August 2019): 372–79. http://dx.doi.org/10.1053/j.seminoncol.2019.08.005.
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