Sitravatinib Targets TYRO3 to Augment the Antitumor Immune Response of PD-1 Blockade in Hepatocellular Carcinoma

Abstract Purpose: Tyrosine kinase inhibitors combined with immune checkpoint blockades produce enhanced antitumor activity in the treatment of advanced hepatocellular carcinoma (HCC). Sitravatinib is a novel multitarget tyrosine kinase inhibitor that targets TYRO3, AXL, and MERTK receptors, c-MET, etc. This study aimed to investigate the antitumor efficacy and immunomodulatory activity of sitravatinib in HCC. Experimental Design: Human HCC cell lines and xenograft models were used to explore the antitumor activity of sitravatinib. Subcutaneous and orthotopic immunocompetent murine HCC models were used to assess the therapeutic efficacy of sitravatinib and PD-1 blockade combination therapy. Cocultures for tumor cells and T cells were performed to verify the immunomodulatory effect of sitravatinib in tumors. Results: Sitravatinib showed potent antitumor activity and immunomodulatory capabilities both invitro and in vivo. Sitravatinib treatment synergized with PD-1 blockade to generate an increased antitumor efficacy, leading to significant enrichment of cytotoxic CD8+ T cells and a reduction in the infiltration of regulatory T cells in tumors. Mechanically, on the one hand, sitravatinib reinforced MHC-I expression by blocking the TYRO3–STAT1 axis, thereby sensitizing tumor cells to T-cell killing. On the other hand, sitravatinib suppressed tumor-secreted IL33 by inhibiting TYRO3 activity in HCC cells, resulting in reduced regulatory T-cell differentiation and consequently liberating CD8+ T-cell cytotoxic capacity. In the clinic, one patient with advanced HCC treated with sitravatinib plus PD-1 blockade achieved near-complete response and remained disease progression free for >2 years. Conclusions: Collectively, we demonstrated a rationale for combining sitravatinib with PD-1 blockade in the treatment for HCC.