Volume 27, No 8, Aug 2017
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 27 Issue 8, August 2017: 1034-1045
ORIGINAL ARTICLES
Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function
Young-hee Lee1,*, Natalia Martin-Orozco1,11,*, Peilin Zheng4,9,10, Jing Li7, Peng Zhang12, Haidong Tan13, Hyun Jung Park5, Mira Jeong6, Seon Hee Chang1, Byung-Seok Kim1, Wei Xiong9,10, Wenjuan Zang7, Li Guo14, Yang Liu12, Zhong-jun Dong7, Willem W Overwijk2, Patrick Hwu2, Qing Yi3,15, Larry Kwak3,16, Zhiying Yang13, Tak W Mak8, Wei Li5, Laszlo G Radvanyi2,11, Ling Ni7, Dongfang Liu4,9 and Chen Dong7
1Department of Immunology
2Department of Melanoma
3Departments of Lymphoma and Myeloma, U.T. MD Anderson Cancer Center, 7455 Fannin St., Houston, TX 77054, USA
4Center for Inflammation and Epigenetics, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA
5Department of Molecular and Cellular Biology,
6Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
7Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China
8The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada
9Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
10The Second Xiangya Hospital, Central South University, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, 139 Renmin Road, Changsha, Hunan 410011, China
11EMD Serono Research and Development Institute, Inc. 45A Middlesex Turnpike, Billerica, MA 01821, USA
12Center for Cancer and Immunology Research, Children's National Health System, Washington DC, 20010 USA
13Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China
14X-KANG United Biopharmaceutical Science & Technology Co. Ltd., Suzhou, Jiangsu 215000, China
15Department of Cancer Biology Betsy B. DeWindt Endowed Chair for Cancer Research, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
16City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, USA
Correspondence: Chen Dong,(chendong@tsinghua.edu.cn)
The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of B7-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8+ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.
10.1038/cr.2017.90
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