Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma

• DOI: 10.1007/s00345-015-1656-7
• Publication Date: 2015-08-07T10:39:38Z
• Authors: Chen Cai; Yi-Fan Xu; Zhen-Jie Wu; Qin Dong; Min-Yu Li; Jason C. Olson; Yaron M. Rabinowitz; Lin-Hui Wang; Yinghao Sun
• Keywords: Male; 0301 basic medicine; Middle Aged; Flow Cytometry; Kidney; Prognosis; Polymerase Chain Reaction; Kidney Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; Humans; Female; RNA, Neoplasm; Carcinoma, Renal Cell; Hepatitis A Virus Cellular Receptor 2; Cell Proliferation; Neoplasm Staging

Renal cell carcinoma (RCC) is the most common cancer of kidney. Evidences have shown that RCC is sensitive to various immunotherapies. Tim-3 plays a role in suppressing Th1-mediated immune responses. However, no study has yet examined the effect of Tim-3 on tumor infiltrating lymphocytes (TILs) in RCC.We investigated the expression and function of Tim-3 on TIL CD4+ T cells and TIL CD8+ T cells from 30 RCC patients.Levels of Tim-3 were significantly increased on both TIL CD4+ T cells and TIL CD8+ T cells and were associated with higher stages of the cancer. Also, GATA-3 and interferon gamma (IFN-γ) were down-regulated, whereas T-bet was up-regulated in TIL Tim-3+ T cells, indicating that Tim-3 expression defined a population of dysfunctional TIL Th1/Tc1 cells. Mechanism analyses showed that TIL Tim-3-expressing CD8+ T cells exhibited impaired Stat5 and p38 signaling pathway. Blocking the Tim-3 pathway restored cell proliferation and increased IFN-γ production in TIL CD4+ and CD8+ T cells of RCC.These results suggest that Tim-3 may be used as a novel target for increasing immune responses in RCC tumor microenvironment.