Combination therapy with anti-T-cell immunoglobulin and mucin-domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma.

Abstract

T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti-TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model. The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology. TIM3 was upregulated in tumor-infiltrating CD8+ and CD4+ T cells in radiation-treated HCa-1-implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P<0.01). Overall survival was improved in the combination group compared with that in the anti-TIM3 or radiation monotherapy groups (median survival time: 52days vs 26 or 38days, respectively, P<0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T-cell activation. CD8+ T-cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment. Anti-TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune-radiotherapy strategy for HCC.