Inhibition of the B7-H3 immune checkpoint limits hepatocellular carcinoma progression by enhancing T lymphocyte-mediated immune cytotoxicity in vitro and in vivo

Purpose The interaction between tumor cells and immune system in hepatocellular carcinoma (HCC) remains unclear. Great clinical achievements have progressed in HCC patients treated with immune checkpoint inhibitors (ICIs) for programmed death-1 and its ligands. However, response efficacy for these therapies is limited, thereby requiring alternative ICI candidates for HCC treatment. B7 homolog 3 protein (B7-H3), an immunoregulatory protein, plays a significant role in tumor immunity and disease progression. In this study, we evaluated the correlation between B7-H3 expression and prognosis of HCC patients, and investigated the therapeutic potential of B7-H3 targeting in HCC. Methods B7-H3 expression was analyzed immunohistochemically in HCC patients, and its relationship with tumor-infiltrating lymphocyte infiltration was assessed. The anti-tumor efficacy of anti-B7-H3 antibody therapy was determined using an in vitro co-culture system and a subcutaneous HCC-bearing murine model. Results We found that B7-H3 overexpressed in tumor cells and positively correlated with poor prognosis in HCC patients. B7-H3 inhibited the infiltration of CD8(+) T cells in tumors. Furthermore, co-culture experiment indicated that inhibiting B7-H3 in tumor cells significantly increased T cells-mediated immune activities and tumor cell killing. Consistently, anti-B7-H3 antibody-treated HCC murine model showed decreased tumor size and enhanced anti-tumor immunity mediated by CD8(+) T cells. Conclusion Altogether, our findings suggest that B7-H3 inhibition in tumor cells restores the immune cytotoxicity of T cells, which in turn promotes apoptosis of target cells. Therefore, B7-H3 serves as a key negative regulator in tumor immunity and the promising clinical utility of B7-H3-based immunotherapies for HCC treatment could be developed.

Automated summary

This study evaluated the expression of B7-H3 protein in HCC patients and its correlation with prognosis, as well as the therapeutic potential of targeting B7-H3 in HCC. It was found that overexpression of B7-H3 in tumor cells was associated with poor prognosis in HCC patients. Inhibiting B7-H3 increased immune activity and tumor cell killing mediated by T cells. Therefore, B7-H3 serves as a key negative regulator in tumor immunity and could be a promising target for immunotherapies in HCC treatment.