Cells and molecules of immune system are the fundamental components of anti-cancer immune responses in the cancer microenvironment. CD8+ T cells migrate to cancer sites to eliminate the cancer cells. An increase in the number of tumor-infiltrating CD8+ T cells in the cancer microenvironment correlates with better clinical outcomes of human cancers. However, induction of inhibitory signaling pathways (immune checkpoints) during CD8+ T cell response to cancer cells results in CD8+ T cell exhaustion that helps in progression of the tumor. Tumor-infiltrating CD8+ T cells express co-inhibitory molecules such as TIM-3 (T cell immunoglobulin and mucin protein 3), which is often co-expresses with PD-1. Both the TIM-3 and PD-1 are now heavily regarded as markers of exhaustion on CD8+ T cells in cancers and in chronic viral infections, although TIM-3 was initially identified on functionally active Th1 cells and effector CD8+ T cells. Ngiow et al. has shown that TIM-3 blockade rejuvenates IFN-γ production in several experimental and carcinogen-induced cancers including the mouse CT-26 cancer model. Still the putative reasons for the higher ratio of tumor-infiltrating CD8+: CD4+ T cells with therapy of anti-mouse TIM-3 monoclonal antibody remain elusive1. As TIM-3 has affinity to galectin-9 that induces apoptosis in both human and murine T cells, negative regulation of T cell immunity through TIM-3 signaling may increase apoptosis of tumor-infiltrating T cells in cancer microenvironment.
Kang C-W, Dutta A, Chang L-Y, et al. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Scientific Reports. 2015;5:15659.