Sitravatinib targets TYRO3 to augment the anti-tumor immune response of PD-1 blockade in hepatocellular carcinoma

Abstract

Purpose: Tyrosine kinase inhibitors (TKIs) combined with immune checkpoint blockades (ICBs) produce enhanced anti-tumor activity in the treatment of advanced hepatocellular carcinoma (HCC). Sitravatinib is a novel multi-target TKI that targets TYRO3, AXL, MERTK (TAM) receptors, c-MET, etc. This study aimed to investigate the anti-tumor efficacy and immunomodulatory activity of sitravatinib in HCC.

Experimental design: Human HCC cell lines and xenograft models were used to explore the anti-tumor 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. Co-cultures for tumor cells and T cells were performed to verify the immunomodulatory effect of sitravatinib in tumors.

Results: Sitravatinib showed potent anti-tumor activity and immunomodulatory capabilities from in vitro to in vivo. Sitravatinib treatment synergized with PD-1 blockade to generate an increased anti-tumor efficacy, leading to significant enrichment of cytotoxic CD8+ T cells as well as reduction of Treg cells infiltration in tumors. Mechanically, on one hand, sitravatinib reinforced MHC-I expression by blocking TYRO3-STAT1 axis, thereby sensitizing tumor cells to T cell liking. On the other hand, sitravatinib suppressed tumor-secreted IL33 by inhibiting TYRO3 activity in HCC cells, resulting in reduced Treg cells differentiation and consequently liberating CD8+ T cell cytotoxic capacity. In the clinic, one advanced HCC patient treated with Sitravatinib plus PD-1 blockade achieved near complete response and remains disease progression-free for more than two years.

Conclusions: Collectively, we demonstrated a rationale for combining sitravatinib with PD-1 blockade in the treatment for HCC.