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

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Abstract

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.

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Data availability

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the further study required.

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Acknowledgements

This research was funded by [Natural Science Foundation of Fujian Province] grant number [2018J01835; 2022J01202] (W.Z.) and [Natural Science Foundation of Fujian Province] grant number [2020J01605] (L.C.).

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Author notes

  1. Zixiong Zhou and Xijie Yu authors have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, Fuzhou, 350122, Fujian, China

    Zixiong Zhou, Xijie Yu, Yuqing Chen, Xiaodan Tan, Wenwen Liu, Wenxi Hua, Lihong Chen & Wenmin Zhang

  2. Diagnostic Pathology Center, Fujian Medical University, 1 Xue Yuan Road, Fuzhou, 350122, Fujian, China

    Yuqing Chen, Wenwen Liu, Wenxi Hua, Lihong Chen & Wenmin Zhang

  3. Department of Pathology, Longyan First Hospital Affiliated to Fujian Medical University, Longyan, 364000, Fujian, China

    Xijie Yu

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  1. Zixiong Zhou
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Contributions

The study was conceived and designed by WZ; XY, YC, XT, WL, and WH performed the experiments; ZZ and WZ wrote the manuscript; ZZ and WZ provided guidance on the study; HC and WZ supervised the research and contributed to the critical review and final approval of the manuscript.

Corresponding authors

Correspondence to Lihong Chen or Wenmin Zhang.

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The authors declare that they have no conflict of interest.

Ethical approval

The research on human specimens was approved by the human research ethics committee of the Fujian Medical University, China (ethical code: FJMU IACUC 2019–45). The animal study was approved by the animal research ethics committee of the Fujian Medical University, China (ethical code: IACUC FJMU 2022–0601), and the corresponding regulatory agencies, and all experiments were carried out following approved guidelines.

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Zhou, Z., Yu, X., Chen, Y. et al. Inhibition of the B7-H3 immune checkpoint limits hepatocellular carcinoma progression by enhancing T lymphocyte-mediated immune cytotoxicity in vitro and in vivo. Clin Transl Oncol 25, 1067–1079 (2023). https://doi.org/10.1007/s12094-022-03013-4

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