Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer.
Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer.
复制标题
DOI：
10.1038/srep15659
复制
发表时间：
2015-10-23
影响因子：
4.6
通讯作者：
Lin CY
中科院分区：
文献类型：
--
作者：
Kang CW;Dutta A;Chang LY;Mahalingam J;Lin YC;Chiang JM;Hsu CY;Huang CT;Su WT;Chu YY;Lin CY
TIM-3的功能是强制CD8+T细胞耗竭，这是一种与肿瘤微环境耐受相关的功能失调状态。在此，我们报道了肿瘤浸润性γ+T细胞中干扰素-CD8活性的TIM-3+T细胞的凋亡。在患有结直肠癌的人中，相对于外周血CD8+T细胞，癌组织中TIM-3+T细胞的比例更高。TIM-3+和TIM-3-癌组织驻留的CD8+T细胞都分泌类似水平的干扰素-γ，尽管与TIM-3-相比，TIM-3+中的凋亡细胞更多。在CT26小鼠结肠癌模型中，大多数肿瘤浸润性CD8+T细胞表达TIM-3，并在TIM-3+细胞中发挥杀伤功能，与TIM-3-细胞相比，TIM-3+细胞分泌更多的效应细胞因子和更多的细胞凋亡。肿瘤细胞分泌Galectin-9，促进肿瘤浸润性CD8+T细胞的凋亡。用抗TIM-3抗体阻断Galectin-9/Tim-3信号通路可减少小鼠肿瘤细胞的凋亡，抑制肿瘤生长。这种阻断也增加了环磷酰胺治疗小鼠肿瘤的疗效。这些结果揭示了TIM-3在体内肿瘤浸润性CD8+T细胞中的未知作用。
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-γ 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-γ 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.