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

Abstract

Background and Aim 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. Methods 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. Results 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: 52 days vs 26 or 38 days, 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. Conclusion 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.

Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma

“…Galunisertib is TGF-β1R inhibitor that is been tested as a single drug and in combination with sorafenib in a phase I-II clinical trial in HCC [ 119 , 120 ]. This molecule has also tested in combination with stereotactic body radiotherapy to promote T-cell antitumor immunity, showing an anti-HCC effect featured by an increase in the CD8 PD1+ TIGIT+ population [ 121 ]. This drug could be an attractive strategy to increase the effect of PD-1/PD-L1 blockade on exhausted T cells after showing ability in increasing intratumoral infiltration of PD-1-expressing cytotoxic T cells.…”

“…The effect of in-vitro blocking of other inhibitory ICs on HCC-specific CD8 T cells have already been tested with encouraging results. Blocking mAbs against TIM3 and LAG3 in association with anti-PD-L1 restore HCC-specific CD8 T cell response with synergic effect [ 21 , 53 , 121 ]. Nevertheless, these combinations have not been assayed in-vivo.…”

A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review

“…Additionally, compared to radiation or an anti-TIM-3 drug alone, the combination of an anti-TIM-3 agent with radiation substantially inhibited tumor development. Furthermore, in line with the tumor growth statistics, the combination group displayed a considerable increase in survival [ 96 ]. Therefore, more emphasis should be paid to combining different ICI and RT to improve the efficacy of therapeutic methods in HCC therapy.…”

Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

“…There are also some studies that showed that immune checkpoint blockade combined with radiotherapy, chemotherapy, and targeted drugs could improve the antitumor efficacy ( Twyman-Saint Victor et al, 2015 ; Ebert et al, 2016 ; Shi et al, 2016 ). In the murine HCC model, combination with anti-TIM-3 and radiotherapy significantly shrink the tumor growth and elongate the OS compared with monotherapy ( Kim et al, 2021 ). In an open-label, randomized, phase III trial (CheckMate 649), nivolumab plus chemotherapy reveals promising prospects than chemotherapy alone with superior OS and progression-free survival (PFS) benefit ( Janjigian et al, 2021 ).…”