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Tumor-expressed B7-H3 mediates the inhibition of antitumor T-cell functions in ovarian cancer insensitive to PD-1 blockade therapy

Cellular & Molecular Immunology volume 17, pages 227–236 (2020)Cite this article

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Abstract

Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers, the majority of patients with solid tumors do not respond well, but the underlying reason remains unclear. Here, we studied ovarian cancer (OvCa), a tumor type generally resistant to current immunotherapies, to investigate PD-1-independent immunosuppression. We found that PD-L1 was not highly expressed in the tumor microenvironment (TME) of human OvCa. Instead, B7-H3, another checkpoint molecule, was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells (APCs), which correlated with T-cell exhaustion in patients. Using ID8 OvCa mouse models, we found that B7-H3 expressed on tumor cells, but not host cells, had a dominant role in suppressing antitumor immunity. Therapeutically, B7-H3 blockade, but not PD-1 blockade, prolonged the survival of ID8 tumor-bearing mice. Collectively, our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8+ T cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition, particularly OvCa patients.

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Acknowledgements

The authors are grateful to Dr. Xueguang Zhang (Soochow University, China) and Jiajia Li (Fudan University Shanghai Cancer Center) for providing the mouse and human OvCa cell lines. This project was funded in part by the Key Program of the National Natural Science Foundation of China (81730039 & 81671460 to L.-P.J.), the National Key Research and Development Program of China (2017YFC1001401 to L.-P.J.), Beijing Municipal Science and Technology Projects (Z181100006318015 and Z181100001318007 to C.D.), Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015 to L.-P.J.), and the National Basic Research Program of China (2015CB943300 to L.-P.J.).

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Authors and Affiliations

  1. Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China

    Dongli Cai & Liping Jin

  2. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China

    Dongli Cai, Shanjuan Hong, Qin Qiao, Qinli Sun, Shan Xie, Ling Ni & Chen Dong

  3. Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China

    Jiaming Li, Tiantian Sun & Li Guo

  4. Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China

    Dingfeng Liu, Pingping Li & Liping Jin

  5. Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China

    Nanan Lyu

  6. Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing, 100084, China

    Chen Dong

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  1. Dongli Cai
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Contributions

D.C., L.N., L.J. and C.D. conceived and designed the study. D.C., J.L., D.L., S.H., Q.Q., Q.S., S.X. and T.S. conducted the experiments. P.L. and N.L. supervised and collected the clinical specimens. D.C. and J.L. analyzed and interpreted the data. L.G. and L.J. provided key materials. D.C., L.N. and C.D. wrote and revised the paper. L.J. and C.D. supervised the study.

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Correspondence to Ling Ni, Liping Jin or Chen Dong.

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Cai, D., Li, J., Liu, D. et al. Tumor-expressed B7-H3 mediates the inhibition of antitumor T-cell functions in ovarian cancer insensitive to PD-1 blockade therapy. Cell Mol Immunol 17, 227–236 (2020). https://doi.org/10.1038/s41423-019-0305-2

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