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Micallef, Peter, Yanling Wu, Marco Bauzá-Thorbrügge, Belén Chanclón, Milica Vujičić, Eduard Peris, C. Joakim Ek, and Ingrid Wernstedt Asterholm. "Adipose Tissue—Breast Cancer Crosstalk Leads to Increased Tumor Lipogenesis Associated with Enhanced Tumor Growth." International Journal of Molecular Sciences 22, no. 21 (November 2, 2021): 11881. http://dx.doi.org/10.3390/ijms222111881.
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We sought to identify therapeutic targets for breast cancer by investigating the metabolic symbiosis between breast cancer and adipose tissue. To this end, we compared orthotopic E0771 breast cancer tumors that were in direct contact with adipose tissue with ectopic E0771 tumors in mice. Orthotopic tumors grew faster and displayed increased de novo lipogenesis compared to ectopic tumors. Adipocytes release large amounts of lactate, and we found that both lactate pretreatment and adipose tissue co-culture augmented de novo lipogenesis in E0771 cells. Continuous treatment with the selective FASN inhibitor Fasnall dose-dependently decreased the E0771 viability in vitro. However, daily Fasnall injections were effective only in 50% of the tumors, while the other 50% displayed accelerated growth. These opposing effects of Fasnall in vivo was recapitulated in vitro; intermittent Fasnall treatment increased the E0771 viability at lower concentrations and suppressed the viability at higher concentrations. In conclusion, our data suggest that adipose tissue enhances tumor growth by stimulating lipogenesis. However, targeting lipogenesis alone can be deleterious. To circumvent the tumor’s ability to adapt to treatment, we therefore believe that it is necessary to apply an aggressive treatment, preferably targeting several metabolic pathways simultaneously, together with conventional therapy.
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McHowat, Jane, Gail Gullickson, Richard G. Hoover, Janhavi Sharma, John Turk, and Jacki Kornbluth. "Platelet-activating factor and metastasis: calcium-independent phospholipase A2β deficiency protects against breast cancer metastasis to the lung." American Journal of Physiology-Cell Physiology 300, no. 4 (April 2011): C825—C832. http://dx.doi.org/10.1152/ajpcell.00502.2010.
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We determined the contribution of calcium-independent phospholipase A2β (iPLA2β) to lung metastasis development following breast cancer injection into wild-type (WT) and iPLA2β-knockout (iPLA2β-KO) mice. WT and iPLA2β-KO mice were injected in the mammary pad with 200,000 E0771 breast cancer cells. There was no difference in primary tumor size between WT and iPLA2β-KO mice at 27 days postinjection. However, we observed an 11-fold greater number of breast cancer cells in the lungs of WT mice compared with iPLA2β-KO animals ( P < 0.05). Isolated WT lung endothelial cells demonstrated a significant increase in platelet-activating factor (PAF) production when stimulated with thrombin [1 IU/ml, 10 min, 4,330 ± 555 vs. 15,227 ± 1,043 disintegrations per minute (dpm), P < 0.01] or TNF-α (10 ng/ml, 2 h, 16,532 ± 538 dpm, P < 0.01). Adherence of E0771 cells to WT endothelial cells was increased by thrombin (4.8 ± 0.3% vs. 70.9 ± 6.3, P < 0.01) or TNF-α (60.5 ± 4.3, P < 0.01). These responses were blocked by pretreatment with the iPLA2β-selective inhibitor ( S)-bromoenol lactone and absent in lung endothelial cells from iPLA2β-KO mice. These data indicate that endothelial cell iPLA2β is responsible for PAF production and adherence of E0771 cells and may play a role in cancer cell migration to distal locations.
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Nguyen, Hong-My, Othon Almanza, and Dipongkor Saha. "Abstract P3-11-01: Oncolytic herpes simplex virus immunovirotherapy eradicates breast cancer and prevents tumor relapse." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–11–01—P3–11–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-11-01.
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Abstract Syngeneic mouse tumor models are critical to investigating new immunotherapeutic modalities and providing a rationale for clinical translation. Oncolytic herpes simplex virus (oHSV) is an emerging treatment strategy for breast cancer. Genetically modified oHSV selectively replicates in cancer cells (sparring healthy cells), induces immunogenic cancer cell death, and stimulates innate/adaptive anti-tumor immune responses. The therapeutic success of oHSV depends on a dynamic interaction between oHSV, the tumor, and the host. Here, we evaluated the anti-tumor effects of G47Δ-IL12, a genetically engineered oHSV expressing interleukin-12 (IL-12), in two orthotopic immunocompetent mouse models of breast cancer, E0771 (some classified this model as luminal B subtype and some as triple-negative) and EMT6 (triple-negative subtype), which are syngeneic to C57BL/6 and BALB/c mice, respectively. Intratumoral G47Δ-IL12 treatment led to complete eradication of orthotopic E0771 and EMT6 mammary tumors and prevention of lung metastases, resulting in 100% long-term survivors, which remained tumor-free during the observation period (>100 days following the last G47Δ-IL12 treatment). In a contralateral orthotopic mammary tumor model, G47Δ-IL12 treatment of primary tumors led to the eradication of both treated and untreated distal tumors, confirming the abscopal and anti-metastatic effect of G47Δ-IL12 virotherapy. All cured mice from G47Δ-IL12-treated groups rejected lethal tumor re-challenge in the contralateral naïve mammary fat pad, indicating successful generation of a protective memory response. In both E0771 and EMT6 models, cell-specific IFN-γ responses and the presence of effector memory T cells (CD4+CD44highCD62Llow phenotype) in spleens of long-term survivors, possibly contributing to tumor relapse prevention. G47Δ-IL12-mediated anti-tumor efficacy was associated with significant increases in CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) (vs. mock group) in both E0771 and EMT6 tumor lesions. G47Δ-IL12 monotherapy also led to a significantly increased CD8+/FoxP3+ ratio (an important parameter for immunotherapy success) in both tumor models. Interestingly, immune cell depletion studies demonstrated that efficacy requires both CD4+ and CD8+ T cells in the E0771 model while only CD8+ T cells were required in the EMT6 model. Conclusions: G47Δ-IL12 monotherapy was effective in eradicating both orthotopic and metastatic tumors and generating long-term protective memory responses in two syngeneic breast cancer models. Treatment efficacy of G47Δ-IL12 was associated with significant immunologic alterations of the TME. G47Δ-IL12 utilized distinct immunologic mechanisms of action to eradicate tumors: CD8+ T cell-dependent action in the EMT6 model, whereas CD4+ and CD8+ T cell-dependent efficacy in the E0771 model. Altogether, our data suggest that G47Δ-IL12 is an efficient inflammatory modulator and beneficially exploits the immune system to eradicate breast tumors. These studies provide the necessary supporting evidence for the clinical translation of this agent into breast cancer patients. Citation Format: Hong-My Nguyen, Othon Almanza, Dipongkor Saha. Oncolytic herpes simplex virus immunovirotherapy eradicates breast cancer and prevents tumor relapse [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-11-01.
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Gong, Jian, Michael Gray, Jeff Hutchins, and Bruce Freimark. "Anti-Tumor Responses By Ibrutinib and Anti-PD-1 Blockade Is Enhanced By Phosphatidylserine-Targeting Antibody Therapy." Blood 128, no. 22 (December 2, 2016): 5379. http://dx.doi.org/10.1182/blood.v128.22.5379.5379.
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Abstract Introduction: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on vascular endothelial cells and tumor cells in the tumor microenvironment, particularly in response to chemotherapy and irradiation. Binding of antibodies targeting PS on the tumor endothelial cells and tumors induces the recruitment of immune cells and engages the immune system to destroy tumor and associated vasculature and by blocking the immunosuppressive action of PS. Recent studies have demonstrated that PS-targeting antibodies enhance the anti-tumor activity of immune checkpoint antibody blockade to CTLA-4 and PD-1 in mouse breast and melanoma tumor models (Freimark et al. Cancer Immunol. Res. 2016; Gray et al. Breast Cancer Res 2016). Ibrutinib is an approved anticancer drug targeting B-cell malignancies that is a selective, covalent inhibitor of the enzyme Bruton's tyrosine kinase(BTK) in B-cell tumors. Data from recent mouse tumor studies demonstrate that ibrutinib in combination with anti-PD-1 antibody blockade inhibits growth of solid tumors (lacking BTK expression) suggesting that ibrutinib may inhibit kinases of the immune system such as interleukin-2 inducible T-cell kinase (ITK), to enhance specific anti-tumor responses (Sagiv-Barfli et al. PNAS 20 2015). Methods: The present study was conducted to evaluate the anti-tumor effects of combination therapy including PS-targeting antibody mouse chimeric 1N11 (mch1N11), ibrutinib (32765) and anti-PD-1 antibody using C57BL/6 mice bearing triple negative E0771 breast tumors. Tumors were staged to an initial volume of ~100mm3and randomized to treatment groups (N=10) with mch1N11 or isotype at 10 mg/kg qw, anti-PD-1 at 2.5 mg/kg qw or ibrunitib 6 mg/kg or vehicle qd x 8. Tumor volumes were measured twice per week to determine tumor growth inhibition (TGI) relative to control treated animals until a maximum volume of 1500-2000mm3. The in vitro sensitivity of E0771 tumor cells to ibrutinib was compared to drug sensitive Jeko-1 lymphoma cells in a 72 hour growth and viability assay. Results: The E0771 cell line is resistant in vitroto 10 mM ibrutinib compared to the drug-sensitive Jeko-1 cell line (Figure 1). Mice bearing E0771 tumors treated with mch1N11, ibrutinib and anti-PD-1 alone had 22.2%, 23.5% and 32.6% TGI respectively. Combination of two agents increased the TGI for mch1N11 and ibrutinib to 30.5%, ibrutinib and anti-PD-1 to 34.5%, mch1N11 and anti-PD-1 to 36.1%. A triple combination therapy had statistically greater TGI compared to control treated mice (59.9%, p = 0.0084) and was greater than single and double combination therapies. Conclusion:Treatment of solid tumors with a combination of inhibitors that target PS, ITK and the PD-1/PD-L1 axis in the tumor microenvironment provides a novel treatment for solid tumors, including triple negative breast cancer. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Gong: Peregrine Pharmaceuticals, Inc.: Employment. Gray:Peregrine Pharmaceuticals, Inc.: Employment. Hutchins:Peregrine Pharmaceuticals, Inc.: Employment. Freimark:Peregrine Pharmaceuticals, Inc.: Employment.
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Sato, Katsutoshi, Stacey J. Baker, E. P. Reddy, and Hanna Y. Irie. "Abstract PD3-08: Novel cancer stem cell inhibitor 108600 modulates tumor immunomicroenvironment of triple negative breast cancer (TNBC)." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD3–08—PD3–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd3-08.
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Abstract 108600, a novel CK2/DYRK1/TNIK inhibitor, targets and inhibits cancer stem cells (CSC) in triple negative breast cancer (TNBC), inhibiting tumor growth and metastases in patient-derived xenograft models. CSC’s have been shown to promote immune evasion of several types of cancer. Specifically, over-expression of CK2 has been shown to promote intratumoral recruitment of myeloid derived suppressor cells. We investigated the effects of 108600 treatment on the immune microenvironment of triple negative breast cancer since targeting CSC’s could promote favorable anti-tumor immune responses and mechanistically contribute to tumor growth inhibition. Methods:C57BL/6 mice bearing murine triple negative E0771 tumors were generated by orthotopic injection and treated either with vehicle control or 108600 for 5 days. Tumor growth was assessed by daily caliper measurement All tumors were recovered at endpoint, and processed for RNA sequencing, flow cytometry or Western blot analysis. Results:108600 treatment significantly inhibited growth of E0771 tumors in vivo, demonstrating for the first time efficacy of 108600 against TNBC in immunocompetent models. 108600 treatment decreased intratumoral phosphorylation and expression of 108600 targets AKT1 (Ser 129) and Cyclin D1, which are substrates of CK2α and Dyrk1, respectively. To further explore nature of transcriptional and signaling pathways affected by 108600 treatment in vivo, RNA sequencing was performed. DGE and subsequent annotation analysis showed that various immune (GO:0006955, GO) and inflammatory (GO:0006954, GO) signaling pathways associated with Stat1 (mmu04062, KEGG) and IFNγ (mmu04060, KEGG) were down-regulated in 108600-treated E0771 tumors. GSEA (Gene set enrichment analysis) indicated that the regulatory T cell (Treg) population (GSE42021, GSE40685) was suppressed by 108600 treatment. To validate these findings, tumor infiltrating leukocytes (TIL) were isolated from vehicle or 108600-treated tumors and analyzed by flow cytometry. CD4, CD25, and FOXP3 expression was used to gate the Treg population. The Treg population was significantly suppressed by 108600 treatment, confirming the RNA sequencing results. 108600 also likely regulates expression of immunomodulatory molecules in TNBC tumor cells since 108600 treatment increased PD-L1 surface expression on E0771 cells in vitro. Conclusions:Our study supports 108600, an inhibitor that targets breast cancer stem cells, as a modulator of the immune microenvironment of TNBC. 108600 suppresses the Treg population among the TIL population and increases tumoral expression of PD-L1. Tregs have been associated with disease progression and metastases of TNBC. Further studies are ongoing to clarify the functional consequences of these changes in the setting of tumor growth inhibition. Synergies between 108600 and checkpoint inhibition are also under investigation and could lead to novel combination therapies for TNBC. Citation Format: Katsutoshi Sato, Stacey J. Baker, E. P. Reddy, Hanna Y. Irie. Novel cancer stem cell inhibitor 108600 modulates tumor immunomicroenvironment of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-08.
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Chen, Xu, and Yong Wang. "GW29-e0771 β-cryptoxanthin prevents H2O2 induced myocardial cell damage by targeting RXRα." Journal of the American College of Cardiology 72, no. 16 (October 2018): C24—C25. http://dx.doi.org/10.1016/j.jacc.2018.08.093.
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Nief, Corrine A., Júlia Sroda Agudogo, Alana Gonzales, Rebecca A. Previs, Smita K. Nair, and Nimmi Ramanujam. "Resetting the tumor microenvironment to favor anti-tumor immunity after local ablation." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2561. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2561.
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2561 Background: Percutaneous tumor ablation is a non-surgical method of tumor destruction that leaves necrotic tumor debris in situ. Tumor associated antigens released after ablation have the potential to initiate a systemic anti-tumor immune response, however the hostile tumor microenvironment hinders antigen presentation and T cell activity. We hypothesized that resetting the tumor microenvironment with oral sodium bicarbonate to decrease tumor acidity and low-dose cyclophosphamide to deplete pro-tumor immune cells would improve the ability of ablation to initiate anti-tumor immunity. Methods: Tumor growth, overall survival, and metastatic burden was assessed in orthotopic tumor models of triple-negative breast cancer (67NR, 4T1, and E0771). Tumor ablation was performed on palpable tumors using percutaneous ethanol injection (PEI) with 6% ethylcellulose to improve retention in the tumor. Surgical excision was used as a negative control to test the role of in situ tumor debris. Before ablation mice were placed on 200 mM of sodium bicarbonate (SB) in their drinking water and received a single intraperitoneal injection of 200 mg/kg of cyclophosphamide (CP). Mice surviving to 60 days after tumor implant without a primary tumor or signs of metastases were considered "cured" and re-challenged with 50e5 tumor cells in the contralateral mammary pad. T cell dependance was assessed with in vivo CD8 depletions. Results: The combination of PEI+SB+CP produced a potent anti-tumor response, curing a majority of mice (5/7 of E0771, 8/12 of 67NR, 7/12 of 4T1). No mice were cured using PEI alone, SB alone, CP alone, or any combination of two therapies (0/51 of E0771, 0/73 of 67NR, 0/75 of 4T1,). Re-challenge tumor growth was hindered in mice cured with PEI+SB+CP. Mice receiving PEI+SB+CP had significantly less metastases and lived longer than mice receiving surgical excision alone or surgical excision with SB+CP. Additionally the anti-metastatic response of PEI+SB+CP was undone when CD8+ T cells were depleted. Conclusions: Here the anti-tumor response of local ablation produced by PEI was enhanced by priming the tumor with low-dose CP and oral SB in metastatic breast cancer. These results suggest that tumor ablation with CP and SB can create a T cell dependent, personalized immune response to a tumor using only low-cost, easily accessible supplies, and the host’s own tumor.
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Wang, Wei, Priyanka S. Rana, Akram Alkrekshi, Katarzyna Bialkowska, Vesna Markovic, William P. Schiemann, Edward F. Plow, Elzbieta Pluskota, and Khalid Sossey-Alaoui. "Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway." Cancers 14, no. 3 (January 27, 2022): 639. http://dx.doi.org/10.3390/cancers14030639.
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Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2lox/lox) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2lox/lox mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC.
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Bohlen, Joseph F., Tyler McClanahan, Sarah Dodd, Linda Vona-Davis, and Emidio E. Pistilli. "E0771 Adenocarcinoma Breast Cancer Tumors Induce Muscle Fatigue and Wasting in C57BL/6 Mice." Medicine & Science in Sports & Exercise 48 (May 2016): 359. http://dx.doi.org/10.1249/01.mss.0000486088.15052.db.
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Knickle, Allison, Andrea Rasmussen, and David W. Hoskin. "Myricetin induces apoptosis mediated by oxidative stress in 4T1 and E0771 mammary cancer cells." Molecular & Cellular Toxicology 16, no. 3 (June 8, 2020): 283–89. http://dx.doi.org/10.1007/s13273-020-00089-3.
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Zhang, Xiyuan, Fabia de Oliveira Andrade, Hansheng Zhang, Idalia Cruz, Robert Clarke, Pankaj Gaur, Vivek Verma, and Leena Hilakivi-Clarke. "Maternal obesity increases offspring’s mammary cancer recurrence and impairs tumor immune response." Endocrine-Related Cancer 27, no. 9 (September 2020): 469–82. http://dx.doi.org/10.1530/erc-20-0065.
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Over 50% of women at a childbearing age in the United States are overweight or obese, and this can adversely affect their offspring. We studied if maternal obesity-inducing high fat diet (HFD) not only increases offspring’s mammary cancer risk but also impairs response to antiestrogen tamoxifen. Female rat offspring of HFD and control diet-fed dams, in which estrogen receptor-positive (ER+) mammary tumors were induced with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), exhibited similar initial responses to antiestrogen tamoxifen. However, after tamoxifen therapy was completed, almost all (91%) tumors recurred in HFD offspring, compared with only 29% in control offspring. The increase in local mammary tumor recurrence in HFD offspring was linked to an increase in the markers of immunosuppression (Il17f, Tgfβ1, VEGFR2) in the tumor microenvironment (TME). Protein and mRNA levels of the major histocompatibility complex II (MHC-II), but not MHC-I, were reduced in the recurring DMBA tumors of HFD offspring. Further, infiltration of CD8+ effector T cells and granzyme B+ (GZMB+) cells were lower in their recurring tumors. To determine if maternal HFD can pre-program similar changes in the TME of allografted E0771 mammary tumors in offspring of syngeneic mice, flow cytometry analysis was performed. E0771 mammary tumor growth was significantly accelerated in the HFD offspring, and a reduction in the numbers of GZMB and non-significant reduction of interferon γ (IFNγ) secreting CD8+ T cells in the TME was seen. Thus, consumption of a HFD during pregnancy increases susceptibility of the female rat and mouse offspring to tumor immune suppression and mammary tumor growth and recurrence.
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Anisiewicz, Artur, Konrad Kowalski, Joanna Banach, Natalia Łabędź, Martyna Stachowicz-Suhs, Aleksandra Piotrowska, Magdalena Milczarek, Dagmara Kłopotowska, Piotr Dzięgiel, and Joanna Wietrzyk. "Vitamin D Metabolite Profile in Cholecalciferol- or Calcitriol-Supplemented Healthy and Mammary Gland Tumor-Bearing Mice." Nutrients 12, no. 11 (November 6, 2020): 3416. http://dx.doi.org/10.3390/nu12113416.
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To analyze if the prometastatic activity of calcitriol (active vitamin D3 metabolite), which was previously observed in a 4T1 breast cancer model, is also found in other breast cancers, and to assess the impact of various schemes of vitamin D supply, we used 4T1 and E0771 mouse metastatic and 67NR nonmetastatic cells in this study. BALB/c and C57BL/6 healthy and tumor-bearing mice were exposed to a control (1000 IU), low- (100 IU), and high- (5000 IU) vitamin D3 diets. Additionally, from day 7 of tumor transplantation, the 1000 and 100 IU groups were gavaged with calcitriol (+cal). After 8 weeks of feeding, plasma levels of 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 were significantly lower in calcitriol-treated and vitamin D-deficient groups than in the control, whereas the levels of all metabolites were increased in the 5000 IU group. The ratio of 25(OH)D3:24,25(OH)2D3 was increased in both calcitriol-treated groups, whereas the ratio of 25(OH)D3:3-epi-25(OH)D3 was increased only in the 100 IU group but decreased in the 5000 IU group. In contrast to E0771, 4T1 lung metastasis was accelerated in all vitamin D-supplemented mice, as well as in the deficient group with an increased inflammatory response. 67NR tumor growth was transiently inhibited in the 1000 IU+cal group, but single metastases were observed in the 5000 and 100 IU groups. Based on the results, we conclude that various schemes of vitamin D supply and vitamin D deficiency led to similar metabolite profiles irrespective of the mice strain and tumor burden. However, depending on the type of breast cancer, different effects on tumor growth and metastasis were noticed.
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Faquan, Li, Wei Liao, and Yiming Zhong. "GW24-e0771 The clinical significance of coronary angiography in the elderly patients with carotid artery stenosis." Heart 99, Suppl 3 (August 2013): A168.4—A169. http://dx.doi.org/10.1136/heartjnl-2013-304613.467.
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Deken, Marcel, Karolina Niewola, Elisa Matas-Rico, Ragini Medhi, Alan Carruthers, Anne Cheasty, Olivier Peyruchaud, et al. "922 A novel autotaxin inhibitor, IOA-289, modulates tumor, immune and stromal cell function and has monotherapy activity in fibrotic cancer models." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A967. http://dx.doi.org/10.1136/jitc-2021-sitc2021.922.
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BackgroundAutotaxin (ATX) is a secreted glycoprotein that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). The expression of both ATX and LPA is elevated in most solid tumors and plasma. LPA signaling directly modulates tumor cell function and contributes to the development of the fibrotic tumor microenvironment, a mechanism by which tumors evade host immunity and impairs response to therapy. IOA-289 is a potent, orally available autotaxin inhibitor which is being developed as a novel treatment of solid tumours burdened with a high degree of fibrosis.MethodsInhibition of ATX activity in human plasma was determined by measuring reduction in LPA species as quantified by LC-MS/MS. In vitro activity on biomarkers of fibrosis was assessed using the BioMAP screen and fibroblast cell cultures. T cell migration was measured using 48-well chemotaxis chambers. PK/PD studies were performed following a single oral dose of IOA-289 in mice, and plasma LPA was used as a PD biomarker. In vivo efficacy was studied in two models of breast cancer, 4T1 and E0771. Bioinformatics used TCGA and GTEX publicly available datasets.ResultsIOA-289 inhibits plasma LPA18:2 with an IC50 of 36nM, with similar results for other LPA species. IOA-289 inhibited fibrosis relevant factors in the BioMAP phenotypic screen, including sIL-6, MCP-1, αSMA, collagen-III, and sVEGF. In further studies, IOA-289 inhibited the secretion of PAI-1 and IL-6 by stimulated fibroblasts. LPA and cancer cell conditioned media inhibited T cell chemotaxis in vitro and the effect was overcome in the presence of IOA-289. The efficacious human dose of IOA-289 was determined following PK/PD studies using plasma LPA as a biomarker of response to ATX inhibition. In vivo studies showed that IOA-289 inhibited metastasis of 4T1 cells, enhanced the infiltration of T cells into 4T1 s.c. implanted tumors and prevented the growth of primary, orthotopically implanted E0771 tumors. Bioinformatics analysis demonstrated elevated ATX expression in pancreatic cancer (PDAC), and PDAC patient plasma showed a correlation of ATX levels with CA-19-9.ConclusionsThe ATX/LPA pathway represents a novel target for anti-cancer therapy with actions on the tumor, immune cell and stromal environment. IOA-289 is a highly potent and selective inhibitor of ATX with demonstrated monotherapy activity in cancer models. Based on the mechanism of action we are investigating combinations of IOA-289 with chemotherapy, immunotherapy and novel agents in ongoing preclinical studies. An acceptable safety and PK profile support the clinical development of IOA-289 which is currently in a phase I clinical trial.Ethics ApprovalThe 4T1 study was approved by The University Claude Bernard Lyon 1 Ethics Board; approval number DR2014-38 (vM). The E0771 study was reviewed and approved by the Institutional Animal Care and Use Committee of the contract research organization (Covance, Ann Arbor, MI, USA), an AAALAC International accredited program.
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Flueh, C., R. Hufnagel, M. Synowitz, and J. Held-Feindt. "P10.05 NKG2DL expression and dormancy in cerebral metastases: impact of chemotherapeutic treatment." Neuro-Oncology 21, Supplement_3 (August 2019): iii41. http://dx.doi.org/10.1093/neuonc/noz126.145.
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Abstract Background: Cerebral metastases are common intracranial lesions and have enormous prognostic impact. In many cases, brain metastases seem to be insensitive to chemotherapeutic treatment and are often source of recurrence. To date, the reasons for this are not entirely known. Dormant tumor cells are a population of non-apoptotic, low proliferating cells, which have the ability to be reactivated and can be the source of recurrence. Another mechanism of tumor cell survival are immunological escape mechanisms, involving the Natural Killer Group 2, member D (nkg2d) receptor-ligand system. In a previous study we were able to show that human brain metastases of pulmonary and breast cancer harbor a significant amount of dormant tumor cells, which often coexpress NKG2D ligands. We now wanted to investigate, whether chemotherapeutic treatment has an effect on expression of dormancy markers and nkg2d ligands. Materials and Methods: The murine breast cancer cell line E0771 and the murine pulmonary cancer cell line LLC were treated with ascending doses of cisplatin and cyclophosphamid, two chemotherapeutics which are also used in humans, for 2 to 10 days in comparison to negative controls. We performed a cytotoxicity assay. Expression of the dormancy-associated markers pdgf, fgf2, hif1alpha, epha5, h2bk and igfbp5 and the nkg2d ligands mult1, h60a, h60b, h60c and raet1b were analyzed by qrtPCR and immunocytochemistry (IHC). Results: Cytotoxicity assay revealed, that cells from both lines died significantly after treatment with Cisplatin in comparison to control conditions. Whereas cyclophosphamide had no effect on dormancy marker and nkg2dl expression, treatment with cisplatin led to a significant upregulation of many nkg2dl and dormancy marker expression in LLC and E0771 in a dose and time dependent manner. Results were confirmed via IHC.Conclusions: Although chemotherapy with cisplatin leads to death of many cells in culture, the surviving cells show a high expression of dormancy markers and of certain nkg2d ligands. Not only acquisition of dormancy but also nkg2d ligand expression might play an important role in chemoresistance of brain metastases. Markers from both groups could therefore be effective therapeutic targets.
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Carrasco, Esther, Jose Manuel Garrido, Pablo Juan Álvarez, Enrique Álvarez-Manzaneda, Rachid Chahboun, Ibtissam Messouri, Consolación Melguizo, Antonia Aránega, and Fernando Rodríguez-Serrano. "Meroxest improves the prognosis of immunocompetent C57BL/6 mice with allografts of E0771 mouse breast tumor cells." Archives of Medical Science 5 (2016): 919–27. http://dx.doi.org/10.5114/aoms.2014.45442.
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Qian, Wei, Jianying Zhou, Roberto Rosato, Jenny Chang, and Ann Anselme. "437 Adenovirus IL-12 and Docetaxel in Combination with Anti-PD1 as an Effective Treatment Strategy for TNBC." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A463. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0437.
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BackgroundIn 2020, over 42,000 women in the US are expected to die from Breast Cancer (BC). Triple Negative Breast Cancer (TNBC), a subtype defined by lack of estrogen receptor (ER), progesterone receptor (PR) and HER2 amplification, account for 15–20% of all BC. TNBC is more prevalent in pre-menopausal African-American and Hispanic women. Currently, chemotherapy is the standard of care for TNBC. Unfortunately, despise the high rate of initial response to neo-adjuvant chemotherapy, TNBC have higher rates of distant recurrence, and few (less than 30%) of the patients survive more than 5 years. Even though this subtype express high levels of PD-L1, the response to checkpoint inhibitor therapy have been modest. We hypothesized that the induction of cell death (Docetaxel) coupled with an immuno-activated milieu (locally injected adv.IL-12) would prime the tumor to respond to Anti-PD1 therapy. In this study, we investigated the effects of initially treating TNBC with a single dose of Docetaxel and adv.IL-12, followed by Anti-PD1 in syngeneic models.MethodsSyngeneic E0771 and 4T1 cell lines were injected in the mammary fat pad of C57BL/6, and Balb/c mice respectively. On day 0, mice in the Triple Combo group received a single dose (20 mg/kg) of Docetaxel and an intratumoral injection (1.25 × 109) of mAdv.IL-12 (a replication defective adenoviral vector containing mouse IL-12 cDNA under the transcriptional control of Rous sarcoma virus long terminal repeat) (provided by Dr. Chen), followed by IP injection Anti-PD1 (InVivoMab anti-mouse PD-1 CD279) on days 3,5,7,10,12, and 14. The other groups, received single therapy following the same procedure. On day 19, Tumor Infiltrating Lymphocytes (TILS) were isolated by Ficoll gradient and submitted for immuno-phenotyping by CyTOF analysis to the HMRI ImmunoMonitoring Core, in addition, tumor lysates were used to measure cytokine expression using Millipore Sigma’s Milliplex MAP Mouse Cytokine/Chemokine Magnetic Beads panel (cat: MCYTMAG-70K). Survival status over time, as well as tumor volume (measured every 3 days) were monitored in both models.ResultsTriple combination inhibited tumor growth in the 4T1 model while significantly delaying E0771 tumor progression. Triple Combo (TC) group had significantly higher number of TILS in both models, while the phenotype and cytokine expression significantly differed. In 4T1, TC increase the infiltration of both CD8 and CD4 effector cells, while significantly decreasing neutrophils. The levels of G-CSF, Rantes were significantly upregulated in this model, while pro-tumorigenic cytokines such as IL-6, LIF, IL-1b, and anti-inflammatory cytokines such as IL-9 and IL-10 were downregulated. In E0771, only effector, and IFN-g producing CD8 levels were increased in TC group. Although TC treated animals survived an average of 18 days more than single Doc treated animals, levels of IL-6, IL-1b, LIF, KC, TNFa and VEGF levels were higher at the end of the study.ConclusionsAd.IL-12 plus Docetaxel followed by Anti-PD1 therapy appears to only be beneficial to a specific subgroup of TNBC. We are actively studying the molecular difference between the two models used in this study, as well as investigating the clinical relevance of these markers using our extensive repertoire of PDXs in a humanized mice model.Ethics ApprovalThe study was approved by the Houston Methodist Research Hospital IACUC committee AUP: 0320-0023
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Newman, Tiffany, Adam Wilson, Elisabeth Tallant, Patricia Gallagher, and Katherine Cook. "Intervention with Probiotics and Muscadine Grape Extract Shifts Western Diet-Associated Metabolic, Microbial, and Inflammatory Parameters to Reduce Breast Tumor Growth." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 344. http://dx.doi.org/10.1093/cdn/nzaa044_043.
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Abstract Objectives Western diet consumption (WD) is associated with increased risk and poor prognosis for breast cancer (BC) due to altered inflammation, metabolism, and microbial colonization. This study will determine whether intervention with probiotics (prbx) and muscadine grape extract (MGE) reduces these effects. Methods Female C57Bl/6 mice were placed on either control diet (CD) or WD (45% fat and 25% sugar). Mice were randomized into six groups per diet: diet alone, antibiotics (abx), prbx, MGE, MGE + abx, and MGE + prbx (n = 8). Prbx groups received 1 × 105 CFU of a 10-strain probiotic 3x weekly. MGE (0.1 phenolics/mL) and abx (5 mg/mL streptomycin, 1 mg/mL ampicillin, 1 mg/mL colistin) were administered in drinking water. Body weights were measured, and feces was collected for 16S sequencing. EchoMRI was performed on mice (total body adiposity) and livers at the end of the study (13 weeks). Immunohistochemistry (IHC) was used to compare mammary gland (MG) and visceral adipose (VA) inflammation (CD68 and MCP-1). To determine whether dietary interventions effected breast cancer growth, female C57Bl6 mice consuming either CD or WD, were injected with 2.5 × 105 E0771-luc triple negative breast cancer cells into the R4/5 MG. Tumors progressed to 100 mm3 prior to treatment. Size was monitored with calipers and IVIS for 21 days. Results MGE + prbx administration in WD-fed mice resulted in reduced body weight. All intervention groups displayed reduced VA and MG weight compared to WD-fed mice. Significant intervention-mediated gut microbial alterations included changes in proportional abundance of Bacteroidetes, Lactococcus, Lactobacillus, and Bifidobacterium taxa. Interventions modulated VA and MG inflammatory markers. Dietary intervention with MGE, prbx, and MGE + prbx reduced E0771 tumor growth rate in CD-fed mice, but not in WD-fed mice. Conclusions Our data suggests that MGE + prbx modulates diet-induced metabolic, inflammatory, and microbial factors. Treatment with MGE + prbx reduced tumor growth rate in CD-fed mice, but not WD. WD-fed mice developed aggressive tumors that treatments were unable to attenuate. Further analyzing tumor tissue will determine whether MGE + prbx altered the tumor microenvironment to improve CD-associated BC prognosis. Funding Sources Chronic Disease Research Fund.
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Brownlie, Demi, Dahlia Doughty-Shenton, Daniel YH Soong, Colin Nixon, Neil O Carragher, Leo M Carlin, and Takanori Kitamura. "Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β." Journal for ImmunoTherapy of Cancer 9, no. 1 (January 2021): e001740. http://dx.doi.org/10.1136/jitc-2020-001740.
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BackgroundMetastatic breast cancer is a leading cause of cancer-related death in women worldwide. Infusion of natural killer (NK) cells is an emerging immunotherapy for such malignant tumors, although elimination of the immunosuppressive tumor environment is required to improve its efficacy. The effects of this “metastatic” tumor environment on NK cells, however, remain largely unknown. Previous studies, including our own, have demonstrated that metastasis-associated macrophages (MAMs) are one of the most abundant immune cell types in the metastatic tumor niche in mouse models of metastatic breast cancer. We thus investigated the effects of MAMs on antitumor functions of NK cells in the metastatic tumor microenvironment.MethodsMAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells. The effects of MAMs on NK cell cytotoxicity towards E0771-LG cells were evaluated in vitro by real-time fluorescence microscopy. The effects of MAM depletion on NK cell activation, maturation, and accumulation in the metastatic lung were evaluated by flow cytometry (CD69, CD11b, CD27) and in situ hybridization (Ncr1) using colony-stimulating factor 1 (CSF-1) receptor conditional knockout (Csf1r-cKO) mice. Finally, metastatic tumor loads in the chest region of mice were determined by bioluminescence imaging in order to evaluate the effect of MAM depletion on therapeutic efficacy of endogenous and adoptively transferred NK cells in suppressing metastatic tumor growth.ResultsMAMs isolated from the metastatic lung suppressed NK cell-induced tumor cell apoptosis in vitro via membrane-bound transforming growth factor β (TGF-β) dependent mechanisms. In the tumor-challenged mice, depletion of MAMs increased the percentage of activated (CD69+) and mature (CD11b+CD27–) NK cells and the number of Ncr1+ NK cells as well as NK cell-mediated tumor rejection in the metastatic site. Moreover, MAM depletion or TGF-β receptor antagonist treatment significantly enhanced the therapeutic efficacy of NK cell infusion in suppressing early metastatic tumor outgrowth.ConclusionThis study demonstrates that MAMs are a main negative regulator of NK cell function within the metastatic tumor niche, and MAM targeting is an attractive strategy to improve NK cell-based immunotherapy for metastatic breast cancer.
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Nalle, Sam, Helen Lam, Ling Leung, Spencer Liang, and Daniel Maslyar. "875 AL009, a fusion protein and multi-Siglec inhibitor, repolarizes suppressive myeloid cells and potentiates anti-cancer effects." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A917. http://dx.doi.org/10.1136/jitc-2021-sitc2021.875.
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BackgroundSialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of cell surface receptors expressed predominantly on myeloid cells that function to promote immune tolerance. Tumors increase the expression of sialic acid glycans and co-opt the immunosuppressive effects of Siglecs, driving tumor resident immune cells toward a cancer permissive phenotype. Due to the overlapping expression profile of Siglec family members on myeloid cells, targeting multiple Siglecs is required for robust efficacy. Here, we present data on AL009, an engineered Siglec-9 extracellular domain-Fc fusion molecule that acts as a sialic acid trap and repolarizes suppressive myeloid cells to activate an anti-cancer immune response.MethodsThe ability of AL009 to competitively block various Siglec-Fc fusion proteins was assessed using cultured human myeloid-derived suppressor cells (MDSCs). MDSC repolarization was analyzed by flow cytometry. MDSCs were co-cultured with activated CD8+ T cells with and without exposure to AL009 and functionally assessed for T-cell activation by flow cytometry and ELISA. In vivo tumor models, including the MC38 and E0771 murine syngeneic subcutaneous models and the B16F10 intravenous lung metastasis model, were used to assess AL009 engineered with a murine Fc (AL009m).ResultsAL009 competitively blocks the ability of at least 5 inhibitory Siglec family members to bind their corresponding sialic acid ligands. When incubated with MDSCs, AL009 promotes CD163 and CD206 downregulation and induces proinflammatory chemokine secretion, consistent with a repolarization effect. Further, AL009 potently relieves MDSC suppression of T cells in a co-culture system. In the MC38 and E0771 murine syngeneic subcutaneous tumor models, AL009m inhibits tumor growth as a monotherapy and in combination with the checkpoint inhibitor anti-PD-L1. In addition, AL009m combines with the tumor antigen targeting antibody TRP-1 in the B16F10 intravenous lung metastasis model to reduce tumor burden.ConclusionsAL009 represents a novel approach to targeting the myeloid cell compartment in oncology by directly repolarizing myeloid cells without cell depletion or limiting the targeting to specific suppressive subpopulations. AL009 has the potential to address tumors that are unresponsive or refractory to standard immunotherapies. These data support further development of AL009 in the clinic with IND enabling studies ongoing.
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Gilliam, Laura A. A., Daniel S. Lark, Lauren R. Reese, Maria J. Torres, Terence E. Ryan, Chien-Te Lin, Brook L. Cathey, and P. Darrell Neufer. "Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction." American Journal of Physiology-Endocrinology and Metabolism 311, no. 2 (August 1, 2016): E293—E301. http://dx.doi.org/10.1152/ajpendo.00540.2015.
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The loss of strength in combination with constant fatigue is a burden on cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and increases mitochondrial H2O2. We hypothesized that the combined effect of cancer and chemotherapy in an immunocompetent breast cancer mouse model (E0771) would compromise skeletal muscle mitochondrial respiratory function, leading to an increase in H2O2-emitting potential and impaired muscle function. Here, we demonstrate that cancer chemotherapy decreases mitochondrial respiratory capacity supported with complex I (pyruvate/glutamate/malate) and complex II (succinate) substrates. Mitochondrial H2O2-emitting potential was altered in skeletal muscle, and global protein oxidation was elevated with cancer chemotherapy. Muscle contractile function was impaired following exposure to cancer chemotherapy. Genetically engineering the overexpression of catalase in mitochondria of muscle attenuated mitochondrial H2O2 emission and protein oxidation, preserving mitochondrial and whole muscle function despite cancer chemotherapy. These findings suggest mitochondrial oxidants as a mediator of cancer chemotherapy-induced skeletal muscle dysfunction.
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Lee, Wen-Jui, Shih-Hsin Tu, Tzu-Chun Cheng, Juo-Han Lin, Ming-Thau Sheu, Ching-Chuan Kuo, Chun A. Changou, et al. "Type-3 Hyaluronan Synthase Attenuates Tumor Cells Invasion in Human Mammary Parenchymal Tissues." Molecules 26, no. 21 (October 29, 2021): 6548. http://dx.doi.org/10.3390/molecules26216548.
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The microenvironment for tumor growth and developing metastasis should be essential. This study demonstrated that the hyaluronic acid synthase 3 (HAS3) protein and its enzymatic product hyaluronic acid (HA) encompassed in the subcutaneous extracellular matrix can attenuate the invasion of human breast tumor cells. Decreased HA levels in subcutaneous Has3-KO mouse tissues promoted orthotopic breast cancer (E0771) cell-derived allograft tumor growth. MDA-MB-231 cells premixed with higher concentration HA attenuate tumor growth in xenografted nude mice. Human patient-derived xenotransplantation (PDX) experiments found that HA selected the highly migratory breast cancer cells with CD44 expression accumulated in the tumor/stroma junction. In conclusion, HAS3 and HA were detected in the stroma breast tissues at a high level attenuates effects for induced breast cancer cell death, and inhibit the cancer cells invasion at the initial stage. However, the highly migratory cancer cells were resistant to the HA-mediated effects with unknown mechanisms.
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Roncato, Francesco, Ofer Regev, Sara W. Feigelson, Sandeep Kumar Yadav, Lukasz Kaczmarczyk, Nehora Levi, Diana Drago-Garcia, et al. "Reduced Lamin A/C Does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis." Cancers 13, no. 10 (May 14, 2021): 2383. http://dx.doi.org/10.3390/cancers13102383.
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The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.
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Wang, Qin, and Ya Yang. "GW26-e0771 Two-dimensional speckle tracking imaging in evaluating clinical value of left ventricular myocardial lesions in patients with metabolic syndrome." Journal of the American College of Cardiology 66, no. 16 (October 2015): C126. http://dx.doi.org/10.1016/j.jacc.2015.06.1078.
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Font, Laura Falceto, Catherine Flores, Jack Figg, Bayli DiVita Dean, Connor Francis, Carmelle Kuizon, and Ginger Moore. "243 Understanding and overcoming the mechanism of resistance to anti-PD-1 monotherapy in brain metastasis." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A262. http://dx.doi.org/10.1136/jitc-2021-sitc2021.243.
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BackgroundThe average overall survival for patients with brain tumors is only 8 to 12 months. For example, the 5-year survival rate for adults over 40 years old living with Glioblastoma multiforme, a type of brain tumor, is only 6%. The brain is also a common organ for metastasis deriving from tumors such as breast cancer. The field of cancer immunotherapy has been making efforts to develop strategies that can target these brain metastases more efficiently than the standard of care in the clinic. Immune checkpoint inhibitors such as anti-PD-1 (anti-programmed cell death-1) therapy are under investigation to treat brain metastases. However, several studies have shown brain metastases to be resistant to anti-PD-1 monotherapy. Our findings have shown that a hematopoietic stem cell (HSC) transfer can overcome this resistance in brain metastasis. Our goal is to elucidate and overcome the mechanism of resistance to anti-PD-1 therapy in brain metastasis.MethodsWe performed both orthotopic mammary fat pad and intracranial (IC) tumor implantations in C57/BL6J mice using a murine breast cancer cell line (E0771). Three days after tumor implantation, we administered the first of four doses of anti-PD-1 therapy delivered five days apart from each other. We measured survival and chemokine (from blood samples) differences between treatments.ResultsWe have observed that orthotopic mammary fat pad tumors are responsive to anti-PD-1 alone. Interestingly, when tumors derived from the same breast cancer cell line are implanted into the brain, they become non-responsive to anti-PD-1 monotherapy. We have also discovered that performing a hematopoietic stem cell transfer overcomes resistance to anti-PD-1 therapy in brain metastases (figure 1). Furthermore, in our preliminary studies we have found that both CD8+ and CD4+ T cells are required for the protective effects of anti-PD-1 against E0771 tumors.Abstract 243 Figure 1A hematopoietic stem cell transfer overcomes resistance to anti-PD-1 in brain metastasisConclusionsBrain metastasis are resistant to anti-PD-1 monotherapy. We have found that a hematopoietic stem cell transfer overcomes resistance to anti-PD-1 in brain metastasis. We hypothesize that, while peripheral T cells successfully remove breast tumors, they fail to mount anti-tumor responses in breast metastatic brain tumors. Therefore, the next step is to understand the mechanism of resistance to anti-PD-1 monotherapy in brain metastasis and to further elucidate the type of T cell immune responses required to overcome this resistance in brain metastasis.Ethics ApprovalIACUC Protocol #201910777
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Vito, Alyssa, Stephanie Rathmann, Natalie Mercanti, Nader El-Sayes, Karen Mossman, and John Valliant. "Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer." International Journal of Molecular Sciences 22, no. 9 (May 3, 2021): 4843. http://dx.doi.org/10.3390/ijms22094843.
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Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.
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Gaymon, Darius O. "Abstract P5-01-12: Physical and visual (social) isolation increases tumor aggressiveness in thermoneutral housing temperatures in murine mammary cancer models." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–01–12—P5–01–12. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-01-12.
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Abstract Correct interpretation of tumor progression data , including the influence of host biology, in mouse models of breast cancer requires models and conditions that faithfully recapitulate human disease and human host status. Our previous attempts to investigate the effects of social isolation have proven inconclusive due to premature mortality in tumor-bearing animals. Those studies were completed in standard temperature (ST), which commonly is 70-72°F (21-22°C) for in vivo murine research based on laboratory animal care and use guidelines. Previous work from the Repasky lab (Kokulus, 2013) , which we have validated (Gaymon, 2020), demonstrates that ST housing results in chronic cold stress and immune suppression mediated by an increase in norepinrephrine (NE) levels, leading to increased tumor aggressiveness. Based on these findings, we investigated the effects of social isolation on BALB/cJ-4T1-luc and C57BL/6J/E0771 tumor progression and metastasis in thermoneutral housing conditions (84-85°F). Mice were first acclimatized to thermoneutral temperature and/or isolation for two weeks in cages that were unilaterally draped to provide physical and visual isolation. In BALB/cJ mice, 4T1-luc tumors were significantly larger in isolated mice compared to group-housed (GH) mice at day 18 (p<.0001). Statistically larger tumors were observed in isolated mice compared to GH mice through day 24 and final tumor masses were also significantly different (p=.004). Spleen masses were not statistically different. In C57BL/6J mice, E0771 tumors were significantly larger in isolates at Day 25 (p=.002). Final tumor masses were statistically (p=.002) different while no difference in spleen sizes were observed. Data on metastasis will be presented at the meeting. We hypothesized that social isolation may perturb immune function and next investigated the growth of 4T1-luc xenograft tumors in NSG mice. 4T1-luc/NSG tumor progression and metastasis data will also be presented at the meeting. We conclude that syngeneic breast tumor growth in immunocompetent BALB/cJ and C57BL/6J mice demonstrates that social isolation is a bona fide stress with sufficient influence to exacerbate breast cancer growth. These data are potentially clinically important due the known relationship of social support to survivorship outcomes in patients and the high-risk of depression and isolation in patients following breast cancer diagnosis. The data may provide additional insight into possible effects of COVID-19 isolation on breast cancer progression. Citation Format: Darius O Gaymon. Physical and visual (social) isolation increases tumor aggressiveness in thermoneutral housing temperatures in murine mammary cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-12.
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Gray, Michael, Jian Gong, Van Nguyen, Takuya Osada, Zachary Hartman, Jeff Hutchins, Bruce Freimark, and Kim Lyerly. "Targeting of phosphatidylserine by monoclonal antibodies augments the activity of paclitaxel and anti-PD1/PD-L1 therapy in the murine breast model E0771." Journal for ImmunoTherapy of Cancer 3, Suppl 2 (2015): P357. http://dx.doi.org/10.1186/2051-1426-3-s2-p357.
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Pearce, Janina V., Jared S. Farrar, Joseph C. Lownik, Bin Ni, Shanshan Chen, Tiffany W. Kan, and Francesco S. Celi. "E0771 and 4T1 murine breast cancer cells and interleukin 6 alter gene expression patterns but do not induce browning in cultured white adipocytes." Biochemistry and Biophysics Reports 18 (July 2019): 100624. http://dx.doi.org/10.1016/j.bbrep.2019.100624.
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Rha, Chan-Su, Hyun Woo Jeong, Saitbyul Park, Siyoung Lee, Young Sung Jung, and Dae-Ok Kim. "Antioxidative, Anti-Inflammatory, and Anticancer Effects of Purified Flavonol Glycosides and Aglycones in Green Tea." Antioxidants 8, no. 8 (August 5, 2019): 278. http://dx.doi.org/10.3390/antiox8080278.
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(1) Background: Extensive research has focused on flavan-3-ols, but information about the bioactivities of green tea flavonols is limited. (2) Methods: In this study, we investigated the antioxidative, anti-inflammatory, and anticancer effects of flavonol glycosides and aglycones from green tea using in vitro cell models. The fractions rich in flavonol glycoside (FLG) and flavonol aglycone (FLA) were obtained from green tea extract after treatment with tannase and cellulase, respectively. (3) Results: FLG and FLA contained 16 and 13 derivatives, respectively, including apigenin, kaempferol, myricetin, and quercetin, determined by mass spectrometry. FLA exhibited higher radical-scavenging activity than that of FLG. FLG and FLA attenuated the levels of intracellular oxidative stress in neuron-like PC-12 cells. The treatment of RAW 264.7 murine macrophages with FLG and FLA significantly reduced the mRNA expression of inflammation-related genes in a dose-dependent manner. Furthermore, FLG and FLA treatments decreased the viability of the colon adenoma cell line DLD-1 and breast cancer cell line E0771. Moreover, the treatment with FLG or FLA combined with paclitaxel had synergistic anticancer effects on the DLD-1 cell line. (4) Conclusions: Flavonols from green tea exerted beneficial effects on health and may be superior to flavan-3-ols.
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Yang, Zelei, Xiaoyun Tang, Guanmin Meng, Matthew Benesch, Martina Mackova, Ana Belon, Jesus Serrano-Lomelin, Ing Goping, David Brindley, and Denise Hemmings. "Latent Cytomegalovirus Infection in Female Mice Increases Breast Cancer Metastasis." Cancers 11, no. 4 (March 29, 2019): 447. http://dx.doi.org/10.3390/cancers11040447.
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Cytomegalovirus (CMV) infects 40–70% of women, but infection has been reported in >95% of breast cancer patients. We investigated the consequences of these observations by infecting mice with mCMV or a negative control medium for 4 days, 11 days or 10 weeks to establish active, intermediate or latent infections, respectively. Syngeneic 4T1 or E0771 breast cancer cells were then injected into a mammary fat pad of BALB/c or C57BL/6 mice, respectively. Infection did not affect tumor growth in these conditions, but latently infected BALB/c mice developed more lung metastases. The latent mCMV infection of MMTV-PyVT mice, which develop spontaneous breast tumors, also did not affect the number or sizes of breast tumors. However, there were more tumors that were multilobed with greater blood content, which had enhanced vasculature and decreased collagen content. Most significantly, mCMV infection also increased the number and size of lung metastases, which showed a higher cell proliferation. Viral DNA was detected in breast tumors and lung nodules although viral mRNA was not. These novel results have important clinical implications since an increased metastasis is prognostic of decreased survival. This work provides evidence that treating or preventing HCMV infections may increase the life expectancy of breast cancer patients by decreasing metastasis.
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Yelek, Caner, Lionel Mignion, Adrien Paquot, Caroline Bouzin, Cyril Corbet, Giulio G. Muccioli, Patrice D. Cani, and Bénédicte F. Jordan. "Tumor Metabolism Is Affected by Obesity in Preclinical Models of Triple-Negative Breast Cancer." Cancers 14, no. 3 (January 23, 2022): 562. http://dx.doi.org/10.3390/cancers14030562.
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Obesity is characterized by an excessive fat mass accumulation associated with multiple disorders, including impaired glucose homeostasis, altered adipokine levels, and hyperlipidemia. Despite clear associations between tumor progression and obesity, the effects of these disorders on tumor metabolism remain largely unknown. Thus, we studied the metabolic differences between tumors of obese and lean mice in murine models of triple-negative breast cancer (E0771 and PY8819). For this purpose, a real-time hyperpolarized 1-13C-pyruvate-to-lactate conversion was studied before and after glucose administration in fasting mice. This work was completed by U-13C glucose tracing experiments using nuclear magnetic resonance (NMR) spectroscopy, as well as mass spectrometry (MS). Ex vivo analyses included immunostainings of major lipid, glucose, and monocarboxylic acids transporters. On the one hand, we discovered that tumors of obese mice yield higher lactate/pyruvate ratios after glucose administration. On the other hand, we found that the same tumors produce higher levels of lactate and alanine from glucose than tumors from lean mice, while no differences on the expression of key transporters associated with glycolysis (i.e., GLUT1, MCT1, MCT4) have been observed. In conclusion, our data suggests that breast tumor metabolism is regulated by the host’s physiological status, such as obesity and diabetes.
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Mariotto, Elena, Giampietro Viola, Roberto Ronca, Luca Persano, Sanja Aveic, Zaver Bhujwalla, Noriko Mori, et al. "Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer." Cancers 10, no. 10 (October 22, 2018): 391. http://dx.doi.org/10.3390/cancers10100391.
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Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of several cancer cell lines. ChoKα1 is particularly overexpressed and hyperactivated in aggressive breast cancer. By NMR analysis, we demonstrated that EB-3D is able to reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast cancer cell proliferation, migration, and invasion. EB-3D induces senescence in breast cancer cell lines through the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1 downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly synergizes with drugs commonly used for breast cancer treatment. The antitumorigenic potential of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast cancer, where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results indicate that EB-3D could be a promising new anticancer agent to improve aggressive breast cancer treatment protocols.
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Rana, Priyanka, Wei Wang, Akram Alkrekchi, Katarzyna Bialkowska, Vesna Markovic, Edward F. Plow, Elzbieta Pluskota, and Khalid Sossey-Alaoui. "Abstract P1-06-02: Targeted deletion of Kindlin-2 in mouse mammary glands inhibits tumor growth, invasion and metastasis downstream of TGF-β/EGF oncogenic signaling pathway." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–06–02—P1–06–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-06-02.
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Abstract Cancer metastasis is a complex process by which cancer cells migrate through the blood and the lymphatic systems to lodge and proliferate in distant sites and organs in the body. Metastasis is the main cause of death in patients suffering from cancer, including those patients with breast cancer. Breast cancer (BC) is the most frequently diagnosed malignancy in women and is one of the leading causes of death due to cancer invasion, metastasis, and resistance to therapies. Among its variants, triple-negative breast cancer (TNBC) is considered the most aggressive due to its early invasive and metastatic properties with poor prognosis. Kindlin-2, which is encoded by Fermitin family homolog 2 gene (FERMT2) has been associated with pathogenesis of several types of cancers of epithelial origin. Our previous studies have addressed the role of Kindlin-2 as a major regulator of the invasion-metastasis cascade in breast cancer by controlling several hallmarks of cancer in tumor cells. The contribution of mammary epithelial cell Kindlin-2 in the mammary glands to the process of tumor progression and metastasis has, however, not been investigated. Accordingly, we generated a floxed mouse strain by targeting the FREMT2 (K2lox/lox) locus using a CRISPR/Cas9-based editing strategy, followed by tissue-specific deletion of the Kindlin-2 in the basal subtype of the mammary epithelial cells (MECs) in the mouse mammary glands by crossing the K2lox/lox mice with K14-cre mice. Loss of Kindlin-2 in the basal MECs had no deleterious effects on mammary glands development, mouse development and fertility and lactation in mice bearing the Kindlin 2-deletetion phenotype and their progeny. However, in a syngeneic mouse model of BC, the loss of Kindlin-2 in MECs inhibited tumor growth and metastasis in mice inoculated with the aggressive murine TNBC E0771 cells when implanted directly in their mammary fat pads. Injecting the E0771 cells via the tail vein of Kindlin-2-deleted mice had, however, no effect on tumor colonization in the lungs, when compared to wild-type mice, clearly supporting a critical role of MECs Kindlin-2 in BC tumor growth and metastasis. Mechanistically, we found the MECs Kindlin-2-mediated inhibition of tumor growth and metastasis is through the regulation of the TGF-β/ERK MAP. kinase signaling axis, in a similar manner that our published studies showed that Kindlin-2 regulates this oncogenic pathway in the BC cells. Thus, our findings strongly suggest that Kindlin-2 supports BC oncogenesis in both the tumor cells and the MECs in the mammary glands, through the regulation of the TGF-β/EGF oncogenic signaling pathway. Therefore, therapeutic strategies targeting Kindlin-2 in both the cancer cells and the mammary glands may be necessary for a successful inhibition of BC tumors. Citation Format: Priyanka Rana, Wei Wang, Akram Alkrekchi, Katarzyna Bialkowska, Vesna Markovic, Edward F Plow, Elzbieta Pluskota, Khalid Sossey-Alaoui. Targeted deletion of Kindlin-2 in mouse mammary glands inhibits tumor growth, invasion and metastasis downstream of TGF-β/EGF oncogenic signaling pathway [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-02.
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Chen, Ivy X., Kathleen Newcomer, Kristen E. Pauken, Vikram R. Juneja, Kamila Naxerova, Michelle W. Wu, Matthias Pinter, et al. "A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade." Proceedings of the National Academy of Sciences 117, no. 38 (September 9, 2020): 23684–94. http://dx.doi.org/10.1073/pnas.2002806117.
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Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+T cells and fewer Gr1+CD11b+myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown inCxcr3−/−mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.
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He, Qi, Maria Jamalpour, Eric Bergquist, Robin L. Anderson, Karin Gustafsson, and Michael Welsh. "Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis." International Journal of Molecular Sciences 22, no. 21 (October 25, 2021): 11478. http://dx.doi.org/10.3390/ijms222111478.
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Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.
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Chongsathidkiet, Pakawat, Karolina Woroniecka, Cosette Dechant, Hanna Kemeny, Xiuyu Cui, Daniel Wilkinson, Selena Lorrey, and Peter Fecci. "BSCI-07. BONE MARROW T-CELL SEQUESTRATION IN THE SETTING OF BRAIN METASTASES." Neuro-Oncology Advances 1, Supplement_1 (August 2019): i2. http://dx.doi.org/10.1093/noajnl/vdz014.006.
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Abstract INTRODUCTION: Brain metastases remain one of the most dreaded consequences of late stage cancer, yet their incidence has risen as survival from primary cancers has improved. We have recently reported that tumors harbored within the brain, specifically, sequester T-cells within the bone marrow as a novel mechanism of immune evasion. Sequestration results from tumor-imposed loss of S1P1 receptor from the T-cell surface. Stabilization of the receptor on T-cells frees T-cells from sequestration and licenses T-cell activating therapies for intracranial tumors. While this phenomenon was initially uncovered in glioblastoma, its role in promoting immune-evasion in brain metastases remains less clear. METHODS: Blood, bone marrow, and tumors were collected from mice bearing intracranial tumors commonly metastatic to the brain, including lung carcinoma (LLC), melanoma (B16F10), or breast carcinoma (E0771) and analyzed by flow cytometry. T-cell S1P1 levels, as well as total T-cell counts were assessed in each compartment. Correlation analyses were conducted between T-cell counts and S1P1 levels on T-cells in the bone marrow across intracranial and subcutaneous murine tumor models. RESULTS: T-cell lymphopenia and accompanying accumulation of T-cells in the bone marrow were observed in the murine models of lung carcinoma, melanoma, and breast carcinoma, but only when these tumor lines were implanted intracranially. Sequestered T-cells in tumor-bearing mice showed decreased surface S1P1 levels in a manner correlating with their sequestration. CONCLUSION: S1P1-mediated bone marrow T-cell sequestration is a novel mode of cancer-induced T-cell dysfunction in intracranial tumors. Preventing receptor internalization abrogates T-cell sequestration and licenses T-cell activating therapies in glioblastoma. Sequestration is now observed in models of brain metastases. Pharmacologic strategies to stabilize S1P1, reverse sequestration, and restore circulating T-cell numbers are anticipated to improve immunotherapeutic efficacy for brain metastases.
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Abe, Shinya, Hiroshi Nagata, Erika J. Crosby, Yoshiyuki Inoue, Kensuke Kaneko, Cong-Xiao Liu, Xiao Yang, et al. "Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003717. http://dx.doi.org/10.1136/jitc-2021-003717.
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BackgroundDespite multimodal adjuvant management with radiotherapy, chemotherapy and hormonal therapies, most surgically resected primary breast cancers relapse or metastasize. A potential solution to late and distant recurrence is to augment systemic antitumor immunity, in part by appropriately presenting tumor antigens, but also by modulating the immunosuppressive tumor microenvironment (TME). We previously validated this concept in models of murine carcinoma treated with a novel predominately microcavitating version of high-intensity focused ultrasound (HIFU), mechanical high-intensity focused ultrasound (M-HIFU). Here we elucidated the mechanisms of enhanced antitumor immunity by M-HIFU over conventional thermal high-intensity focused ultrasound (T-HIFU) and investigated the potential of the combinatorial strategy with an immune checkpoint inhibitor, anti-PD-L1 antibody.MethodsThe antitumor efficacy of treatments was investigated in syngeneic murine breast cancer models using triple-negative (E0771) or human ErbB-2 (HER2) expressing (MM3MG-HER2) tumors in C57BL/6 or BALB/c mice, respectively. Induction of systemic antitumor immunity by the treatments was tested using bilateral tumor implantation models. Flow cytometry, immunohistochemistry, and single-cell RNA sequencing were performed to elucidate detailed effects of HIFU treatments or combination treatment on TME, including the activation status of CD8 T cells and polarization of tumor-associated macrophages (TAMs).ResultsMore potent systemic antitumor immunity and tumor growth suppression were induced by M-HIFU compared with T-HIFU. Molecular characterization of the TME after M-HIFU by single-cell RNA sequencing demonstrated repolarization of TAM to the immunostimulatory M1 subtype compared with TME post-T-HIFU. Concurrent anti-PD-L1 antibody administration or depletion of CD4+ T cells containing a population of regulatory T cells markedly increased T cell-mediated antitumor immunity and tumor growth suppression at distant, untreated tumor sites in M-HIFU treated mice compared with M-HIFU monotherapy. CD8 T and natural killer cells played major roles as effector cells in the combination treatment.ConclusionsPhysical disruption of the TME by M-HIFU repolarizes TAM, enhances T-cell infiltration, and, when combined with anti-PD-L1 antibody, mediates superior systemic antitumor immune responses and distant tumor growth suppression. These findings suggest M-HIFU combined with anti-PD-L1 may be useful in reducing late recurrence or metastasis when applied to primary tumors.
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Elder, Alan, Alexander Stoller, Kelsey Kines, and Traci Lyons. "457 Semaphorin7a expression in breast cancer promotes susceptibility to immune checkpoint blockade." Journal of Clinical and Translational Science 6, s1 (April 2022): 90. http://dx.doi.org/10.1017/cts.2022.267.
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OBJECTIVES/GOALS: The goal of this study is to decipher the mechanisms by which breast cancers evade the immune system to facilitate metastasis through the lymphatic vasculature. We believe this is caused, in part, by semaphorin 7A (SEMA7A) as its expression is associated with increased lymphatic vessels, tumor-associated macrophages, and metastasis in breast cancer. METHODS/STUDY POPULATION: We have observed that breast cancer cells, lymphatics, and macrophages exhibit SEMA7A-dependent expression of PD-L1 in vitro, which may make SEMA7A+ tumors more sensitive to anti-PD-1/PD-L1 immunotherapies. Therefore, we utilized multiple orthotopic, immunocompetent mouse models to determine if SEMA7A expression makes tumors more susceptible to immune checkpoint blockade. E0771 and 66cl4 mouse mammary carcinoma cells were injected orthotopically into the #4 mammary fat pads. Once tumors reached 50-100 mm^3 mice were injected intraperitoneally with 250ug of anti-PD-1, anti-PD-L1, or IgG control every third day. Tumors were measured with calipers every other day and harvested for flow cytometry to determine the effect of immune checkpoint blockade on the TME in SEMA7A+ tumors. RESULTS/ANTICIPATED RESULTS: We reveal that growth of SEMA7A overexpressing (OE) tumors, but not controls, was significantly slowed with both anti-PD-1 and anti-PD-L1 treatments. Flow cytometric analysis of cells from the TME revealed increased LECs, TAMs, and PoEMs in SEMA7A+ tumors, compared to controls – all populations had higher PD-L1 expression, which was decreased with both anti-PD-1 or anti-PD-L1. We also observed a decrease in PD-L1 expression on the tumor cells with treatment. Furthermore, LEC, TAM, and PoEM presence was decreased within the TME alongside increased presence of activated CD4 and CD8 T cells. Collectively, our results suggest that SEMA7A expression in breast cancers activates a major pathway associated with immune evasion and helps to establish a pro-tumor microenvironment. DISCUSSION/SIGNIFICANCE: SEMA7A expression establishes a pro-tumor microenvironment, which can be targeted with readily available FDA approved drugs such as immune checkpoint-based therapies. Since SEMA7A+ breast cancers have high rates of metastasis, more specific treatments for these patient populations should be explored.
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Zhao, Wei, and Janos Zempleni. "Adipocyte-Derived Exosomes Increase the Growth of Breast Tumors in Obese Mice." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 367. http://dx.doi.org/10.1093/cdn/nzaa044_066.
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Abstract Objectives 1) We assessed whether the secretion and cargos of exosomes are distinct in obese and lean mice. 2) We assessed whether adipocyte-derived exosomes increase the size of tumors of the mammary gland in mice. Methods Female tamoxifen-inducible adipose-specific TSG101 conditional knockout mice (TSG KO) were initiated on an AIN-93G-based 50% high fat (HFD) or 15.8% low fat (LFD) at age 3 weeks and continued on these diets for 10 weeks. At age 4 weeks, mice were injected with tamoxifen or vehicle (TSG+), followed by the injection of 1.8*106 murine breast adenocarcinoma E0771 cells into the mammary gland fat pad 10 days after tamoxifen injection. Loss and gain of TSG101 and Cre, respectively, in inguinal subcutaneous adipose tissue were confirmed by RT-qPCR. Tumors were excised and their size was assessed using a caliper and by weight. H&E staining was used to assess the tumor type. Exosomes were isolated from plasma by an ExoQuick Plasma Prep kit, authenticated by western blot analysis and counted using a Nanosight tracker. The statistical analysis was performed by one-way ANOVA and Least Significant Differences posthoc test using a significance level of P < 0.05. Results HFD led to an increase in breast tumor size, which was diminished in adipose-specific TSG101 KO fed HFD: The size of mammary tumors in TSG+ fed HFD increased by 198% compared to TSG+ fed LFD (P < 0.05), whereas tumor size decreased by 58% TSG101 KO fed HFD compared to TSG+ fed HFD (P < 0.05). HFD led to an increase in adipose-derived exosomes that was reduced by TSG101 KO: The expression of ASC-1, a marker for adipose-derived exosomes in plasma exosomes increased by 58% in TSG+ fed HFD compared to TSG+ fed LFD, and decreased by 29% in TSG KO fed HFD compared to TSG+ fed HFD (P < 0.05). Plasma exosomes tested positive for exosome markers, CD63, CD81 and HSP70 and negative for a non-exosome marker, calnexin. H&E staining suggested that the tumors observed in all mice were adenocarcinomas. Tumor numbers were not affected by TSG101 and diet. Conclusions HFD increases the growth of mammary tumors in mice and the diet effect depends on exosome biogenesis in adipose tissue. We speculate that adipose-derived exosomes promote tumor growth but not metastasis. Funding Sources NIFA, NIH, and USDA. J.Z. is a consultant for PureTech Health.
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Chaib, Mehdi, Liza Makowski, John Yarbro, Laura Sipe, and Deidre Daria. "682 PKC agonism restricts innate immune suppression, promotes antigen cross-presentation and synergizes with agonistic CD40 therapy in breast cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A710. http://dx.doi.org/10.1136/jitc-2021-sitc2021.682.
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BackgroundImmunotherapies that reinvigorate T cell responses have transformed the treatment of many cancers showing unprecedented durable antitumor responses. However, most patients do not respond to immunotherapy due in part to immunosuppression. Immunotherapy non-responders have high levels of circulating myeloid-derived suppressor cells (MDSCs)- an innate cell population that expands in pathological conditions such as cancer and suppresses T cells via production of immunosuppressive factors. In contrast, immunotherapy success is dependent on the ability of antigen-presenting cells (APCs) to cross-present tumor antigens to cytotoxic T cells. Immunogenic cross-presentation by APCs requires a specific subtype of dendritic cells (DCs) called conventional DC1 (cDC1) which are dysfunctional in cancer. Novel ways to increase cDC1 function are promising and under active investigation. One of these ways is ligation of CD40 which is primarily expressed by myeloid cells and its agonism leads to myeloid cell activation. Thus, targeting MDSCs while simultaneously expanding cross-presenting DCs represents a promising strategy that, when combined with agonistic CD40, will likely result in long-lasting protective immunity.MethodsUsing in vitro, ex vivo, in vivo and adoptive transfer systems, we investigated the effect of PKC agonists PEP005 and prostratin on MDSC expansion, differentiation to APC-like cells and recruitment to the TME. MDSC suppressive capacity was investigated using functional coculture assays with CD8+ T cells. Furthermore, we assessed the effect of PKC agonists on MDSC cross-priming capacity using in vitro coculture assay with OT-I CD8+ T cells as well as adoptive transfer experiments. We also investigated the effect of PKC agonists on cDC1 expansion from the BM in vitro and in vivo. Finally, we tested the efficacy of PKC agonism in combination with agonistic CD40 using the E0771 murine breast cancer orthotopic mouse model.ResultsHerein, we show that PKC agonists decreased MDSC expansion from hematopoetic progenitors in the BM and induced M-MDSC differentiation to an APC-like phenotype that expresses cDC1-related markers and the transcription factor Irf8. Simultaneously, PKC agonists favored cDC1 expansion at the expense of cDC2 and plasmocytoid DCs (pDC). Functionally, PKC agonists blunted MDSC suppressive function of T cells and promoted MDSC cross-priming capacity. Finally, combination of PKC agonism with agonistic CD40 mAb resulted in a marked reduction in tumor growth while synergistically increased intratumoral activated CD8+ T cells and tissue-resident memory CD8+ T cells.ConclusionsIn sum, we propose a novel promising strategy to simultaneously target MDSCs and promote APC function that may have potential clinical relevance in cancer patients.
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Zhang, Hua, Weihua Zhang, Yu Zhang, and Jing Li. "GW26-e0775 Hypoalbuminemia complicated with pulmonary embolism 3 cases." Journal of the American College of Cardiology 66, no. 16 (October 2015): C241. http://dx.doi.org/10.1016/j.jacc.2015.06.931.
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Anlin, Lv. "GW25-e0271 The progress of cardiac stem cell study." Journal of the American College of Cardiology 64, no. 16 (October 2014): C63. http://dx.doi.org/10.1016/j.jacc.2014.06.302.
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Putkiewicz, J., J. L. Padilla Garcia, A. Obrycka, A. Lorens, A. Piotrowska, M. Zgoda, and H. Skarzynski. "E077 Questionnaire for Partial Deafness Treatment (PDT) satisfaction assessment." International Journal of Pediatric Otorhinolaryngology 75 (May 2011): 75. http://dx.doi.org/10.1016/s0165-5876(11)70385-8.
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Li, Xiaoyan, Caihong Qu, Erhong Zhang, Ying Lu, Yuxing Liu, and Yongbo Tang. "GW26-e0711 Ticagrelor Prevents Endothelial Dysfunction of Aortas in Hypertension Rats." Journal of the American College of Cardiology 66, no. 16 (October 2015): C69. http://dx.doi.org/10.1016/j.jacc.2015.06.1287.
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Hou, Liang, and Yanchun Ding. "GW26-e0776 Regulation of NOD1/RIP2 Signal Pathway in Macrophage Inflammatory Activation." Journal of the American College of Cardiology 66, no. 16 (October 2015): C51—C52. http://dx.doi.org/10.1016/j.jacc.2015.06.1219.
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Ziyu, Zheng, Jianghui Liu, Ruibin Cai, Yingxiong Huang, Zi Ye, Jia Xu, and Hong Zhan. "GW25-e0772 Risk Factors Of Postoperative Mortality Of Ruptured Abdominal Aortic Aneurysms." Journal of the American College of Cardiology 64, no. 16 (October 2014): C201. http://dx.doi.org/10.1016/j.jacc.2014.06.925.
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Kim, Jang Young, and Jung Ran Choi. "GW28-e0971 Serum fibroblast growth factor 21 and new-onset metabolic syndrome." Journal of the American College of Cardiology 70, no. 16 (October 2017): C82. http://dx.doi.org/10.1016/j.jacc.2017.07.286.
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Zhao, Na, Yong Zhang, Xuejun Zhang, and Junkui Wang. "GW29-e0751 Sestrin2 is involved in endoplasmic reticulum stress induced atrial fibrillation." Journal of the American College of Cardiology 72, no. 16 (October 2018): C23. http://dx.doi.org/10.1016/j.jacc.2018.08.088.
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Jia, Qian, Jinju Jia, and Hongbin Liu. "GW26-e0773 Hemodynamics analysis of local carotid artery plaques and implication to plaques." Journal of the American College of Cardiology 66, no. 16 (October 2015): C122. http://dx.doi.org/10.1016/j.jacc.2015.06.473.
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