The combination of CD8 and TIM3 expression to predict survival outcomes in hepatocellular carcinoma.

Abstract

543 Background: CD8+ T cells have anti-tumor immunity in a variety of cancers including hepatocellular carcinoma (HCC). Tumor-infiltrating CD8+ T cells express immune checkpoint proteins and focus on a therapeutic targeting. T cell immunoglobulin and mucin domain protein 3 (TIM3) has been reported to be associated with suppression of anti-tumor immunity, poor prognosis, and tumor progression in HCC, resulting in up-regulation on exhausted CD8+ T cells. As the exhausted T cells showed a decrease of effector cytokine production and cytolytic activity, leading to the tumor progression, TIM3 is one of the most important exhaustion markers. In the present study, we investigated the role of CD8 and TIM3 as a prognostic biomarker in HCC. Methods: We analyzed 474 HCC patients with clinical and transcriptomic data from The Cancer Genome Atlas (TCGA: n=359) and GSE 76427 (n=115) to examine associations between CD8, TIM3, and programmed death receptor-1/programmed cell death ligand 1 (PD-1/PD-L1) expression and survival outcomes. Each gene was divided into low- and high-expression groups using the tertiles of gene expression. Results: The patients with high CD8 and low TIM3 expression were associated with better overall survival (OS) (P=0.021 and P=0.025, respectively) in TCGA, while PD-1/PD-L1 were not associated with OS (P=0.306 and P=0.318, respectively). Moreover, the patients with high CD8 and low TIM3 expression were validated in GSE dataset (P=0.014 and P=0.009, respectively). The patients with high CD8 and low TIM3 expression were associated with improved OS compared with the overall HCC patient (P=0.008). Among the patients with high CD8 expression, low TIM3 expression (non-exhausted CD8+ T cells) was associated with better OS (P=0.009), but PD-1/PD-L1 were not associated with OS (P=0.491 and P=0.772, respectively). Finally, multivariate analysis showed that the patients withnon-exhausted CD8+ T cells were significantly superior for the survival outcomes (Hazard ratio=2.80, 95% CI=1.27–6.19, P=0.01). Conclusions: High CD8 and low TIM3 expression is associated with better OS in HCC than PD-1/PD-L1, suggesting that CD8 and TIM3 are useful biomarkers for predicting HCC prognosis. Restoring exhausted T cells via the suppression of TIM3 is a promising strategy for cancer treatment, which become a breakthrough in the cancer immunotherapy.