Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function

Young Hee Lee, Natalia Martin-Orozco, Peilin Zheng, Jing Li, Peng Zhang, Haidong Tan, Hyun Jung Park, Mira Jeong, Seon Hee Chang, Byung Seok Kim, Wei Xiong, Wenjuan Zang, Li Guo, Yang Liu, Zhong Jun Dong, Willem W. Overwijk, Patrick Hwu, Qing Yi, Larry Kwak, Zhiying YangTak W. Mak, Wei Li, Laszlo G. Radvanyi, Ling Ni, Dongfang Liu, Chen Dong

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1034-1045
Number of pages12
JournalCell Research
Volume27
Issue number8
DOIs
StatePublished - Aug 1 2017

Keywords

  • B7-H3
  • Checkpoint inhibition
  • Immunotherapy
  • Tumor immunity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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