Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep15659
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Funding
- National Science Council, Ministry of Science & Technology, Taiwan [MOST 103-2811-B-182A-004, MOST 104-2811-B-182A-008, NSC-100-3112-B-182-001, NSC102-2314-B-182-024-MY2]
- NHRI project from National Health Research Institute, Taiwan [NHRI-EX103-10101BI]
- Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan [CMRPG392133, CMRPG3C0651, CMRPG3C0652, CMRPG3D0041]
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TIM-3 functions to enforce CD8+ T cell exhaustion, a dysfunctional state associated with the tolerization of tumor microenvironment. Here we report apoptosis of IFN-gamma competent TIM-3+ population of tumor-infiltrating CD8+ T cells in colon cancer. In humans suffering from colorectal cancer, TIM-3+ population is higher in cancer tissue-resident relative to peripheral blood CD8+ T cells. Both the TIM-3+ and TIM-3-cancer tissue-resident CD8+ T cells secrete IFN-gamma of comparable levels, although apoptotic cells are more in TIM-3+ compared to TIM-3-population. In mouse CT26 colon tumor model, majority of tumor-infiltrating CD8+ T cells express TIM-3 and execute cytolysis function with higher effector cytokine secretion and apoptosis in TIM-3+ compared to TIM-3- population. The tumor cells secrete galectin-9, which increases apoptosis of tumor-infiltrating CD8+ T cells. Galectin-9/TIM-3 signaling blockade with anti-TIM-3 antibody reduces the apoptosis and in addition, inhibits tumor growth in mice. The blockade increases therapeutic efficacy of cyclophosphamide to treat tumor in mice as well. These results reveal a previously unexplored role of TIM-3 on tumor-infiltrating CD8+ T cells in vivo.
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