The immunosuppression of tumor infiltrating lymphocytes (TILs) is associated with rapid progress of hepatitis B virus related hepatocellular carcinoma (HBV-HCC). The inhibition molecules of T lymphocyte surface are closely related to the exhaustion of T lymphocytes. T-cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) and programmed death-1 (PD-1) are the two most important inhibition molecules of T cells but their roles in HBV-HCC-TILs are still poorly understood. In this study, we showed that Tim-3 and PD-1 up-regulated expressed on CD4+ and CD8+ TILs in HBV-HCC patients and most Tim-3+ TILs coexpressed PD-1 . Tim-3+ and PD-1+ TILs greatly decreased the secretions of IFN-gamma and TNF-alpha. The frequency of CD8+ TILs also decreased in HCC tumor tissue . Moreover, the expressions of Tim-3 and PD-1 on TILs negatively correlated with the disease free survival (DFS) of HCC patients. In functional study, we found direct blocking Tim-3 plus PD-1 pathways in vitro significantly enhanced cell proliferations and IFN-gamma, TNF-alpha secretion of TILs in HCC. We further showed that elevated IFN-gamma and TNF-alpha production inhibited the growth of HepG2 cells and made them stay at G0 phase.

Conclusion: Direct blockade of Tim-3 plus PD-1 restore the antitumor immunity of TILs and inhibit HCC cells growth into senescence, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches in HBV-HCC.

CITATION INFORMATION: Hu A, Liu F, Zhu X, He X. Blockade of Tim-3 and PD-1 Reverses Dysfunctions of Tumor Infiltrating Lymphocytes in HBV Related Hepatocellular Carcinoma. Am J Transplant. 2017;17 (suppl 3).

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