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B7-H3 confers resistance to Vγ9Vδ2 T cell-mediated cytotoxicity in human colon cancer cells via the STAT3/ULBP2 axis

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Abstract

Immunotherapy based on γδT cells has limited efficiency in solid tumors, including colon cancer (CC). The immune evasion of tumor cells may be the main cause of the difficulties of γδT cell-based treatment. In the present study, we explored whether and how B7-H3 regulates the resistance of CC cells to the cytotoxicity of Vγ9Vδ2 (Vδ2) T cells. We observed that B7-H3 overexpression promoted, while B7-H3 knockdown inhibited, CC cell resistance to the killing effect of Vδ2 T cells in vitro and in vivo. Mechanistically, we showed that B7-H3-mediated CC cell resistance to the cytotoxicity of Vδ2 T cells involved a molecular pathway comprising STAT3 activation and decreased ULBP2 expression. ULBP2 blockade or knockdown abolished the B7-H3 silencing-induced increase in the cytotoxicity of Vδ2 T cells to CC cells. Furthermore, cryptotanshinone, a STAT3 phosphorylation inhibitor, reversed the B7-H3 overexpression-induced decrease in ULBP2 expression and attenuated the killing effect of Vδ2 T cells on CC cells. Moreover, there was a negative correlation between the expression of B7-H3 and ULBP2 in the tumor tissues of CC patients. Our results suggest that the B7-H3-mediated STAT3/ULBP2 axis may be a potential candidate target for improving the efficiency of γδT cell-based immunotherapy in CC.

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Acknowledgements

The authors thank all the members of the department of gastroenterology, general surgery, and pathology of the First Affiliated Hospital of Soochow University for their help in collecting clinical samples.

Funding

This study was supported by the National Natural Science Foundation of China (81802843, 81672372, 81372276); Colleges and Universities Natural Science Research Project of Jiangsu Province (18KJB320023, 17KJA310004); Suzhou Science & Technology plan project (SYS2019035, SYS201747, SS2019077).

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Authors and Affiliations

  1. Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, 215100, Jiangsu, China

    Huimin Lu, Hongya Wu, Yanzheng Gu, Xueguang Zhang, Guangbo Zhang, Tongguo Shi & Weichang Chen

  2. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China

    Huimin Lu, Yanchao Ma, Jin Shen, Juntao Li, Nan Gao & Weichang Chen

  3. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China

    Huimin Lu, Yanchao Ma, Tongguo Shi & Weichang Chen

  4. Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China

    Yanchao Ma & Tongguo Shi

  5. Suzhou Red Cross Blood Center, 355 Shizi Road, Suzhou, China

    Mingyuan Wang

  6. 50 Donghuan Road, Suzhou, 215100, Jiangsu, China

    Weichang Chen

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  1. Huimin Lu
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Contributions

HL, TS and WC designed the experiments; HL, YM, HW, and JL performed most of the experiments; MW and YG contributed to provide clinical samples; YM, NG, and YG assisted with experiments and analysis of the data; XZ and GZ provided administrative, technical, or material support. HL, TS, and WC wrote the manuscript.

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Correspondence to Tongguo Shi or Weichang Chen.

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The authors declare that they have no competing interests.

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All animal experiments were performed under the institutional guidelines of the Institutional Animal Care and Use Committee of Soochow University. The experiments involving in tissue samples of patients with CC were approved by the Institutional Review Board of the First Affiliated Hospital of Soochow University.

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Lu, H., Ma, Y., Wang, M. et al. B7-H3 confers resistance to Vγ9Vδ2 T cell-mediated cytotoxicity in human colon cancer cells via the STAT3/ULBP2 axis. Cancer Immunol Immunother 70, 1213–1226 (2021). https://doi.org/10.1007/s00262-020-02771-w

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