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 Yang; Tak W. Mak; Wei Li; Laszlo G. Radvanyi; Ling Ni; Dongfang Liu; Chen Dong

doi:10.1038/cr.2017.90

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 journal › Article › peer-review

235 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 language	English (US)
Pages (from-to)	1034-1045
Number of pages	12
Journal	Cell Research
Volume	27
Issue number	8
DOIs	https://doi.org/10.1038/cr.2017.90
State	Published - Aug 1 2017

Keywords

B7-H3
Checkpoint inhibition
Immunotherapy
Tumor immunity

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1038/cr.2017.90

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Lee, Y. H., Martin-Orozco, N., Zheng, P., Li, J., Zhang, P., Tan, H., Park, H. J., Jeong, M., Chang, S. H., Kim, B. S., Xiong, W., Zang, W., Guo, L., Liu, Y., Dong, Z. J., Overwijk, W. W., Hwu, P., Yi, Q., Kwak, L., ... Dong, C. (2017). Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Research, 27(8), 1034-1045. https://doi.org/10.1038/cr.2017.90

Lee, YH, Martin-Orozco, N, Zheng, P, Li, J, Zhang, P, Tan, H, Park, HJ, Jeong, M, Chang, SH, Kim, BS, Xiong, W, Zang, W, Guo, L, Liu, Y, Dong, ZJ, Overwijk, WW, Hwu, P, Yi, Q, Kwak, L, Yang, Z, Mak, TW, Li, W, Radvanyi, LG, Ni, L, Liu, D & Dong, C 2017, 'Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function', Cell Research, vol. 27, no. 8, pp. 1034-1045. https://doi.org/10.1038/cr.2017.90

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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.",

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AU - Tan, Haidong

AU - Park, Hyun Jung

AU - Jeong, Mira

AU - Chang, Seon Hee

AU - Kim, Byung Seok

AU - Xiong, Wei

AU - Zang, Wenjuan

AU - Guo, Li

AU - Liu, Yang

AU - Dong, Zhong Jun

AU - Overwijk, Willem W.

AU - Hwu, Patrick

AU - Yi, Qing

AU - Kwak, Larry

AU - Yang, Zhiying

AU - Mak, Tak W.

AU - Li, Wei

AU - Radvanyi, Laszlo G.

AU - Ni, Ling

AU - Liu, Dongfang

AU - Dong, Chen

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AB - 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.

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

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Keywords

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