In search of better immunotherapy for ovarian cancer (OvCa), Cai et al. investigated the role of the negative regulator B7-H3. Unlike PD-L1, B7-H3 was highly expressed on human OvCa cells and the TME, and correlated positively with an exhausted PD-1+ CD8+ TIL phenotype. KO of B7-H3 in a murine ID8 OvCa cell line was sufficient to prevent tumor growth and prolong survival in both subcutaneous and IP models compared to wild-type ID8, while B7-H3 KO in recipient mice had little impact on ID8 growth. Mice challenged with wild-type ID8 tumors and treated with anti-B7-H3 had significantly improved survival compared to anti-PD-1 treatment.
Contributed by Katherine Turner
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.
Author Info: (1) Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. (2) S
Author Info: (1) Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. (2) Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China. (3) Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China. (4) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. (5) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. (6) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. (7) Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China. (8) Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. (9) Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China. (10) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. (11) Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China. (12) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. lingni@tsinghua.edu.cn. (13) Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China. jinlp01@163.com. Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China. jinlp01@163.com. (14) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. chendong@tsinghua.edu.cn. Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing, 100084, China. chendong@tsinghua.edu.cn.
