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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Acknowledgements
This work was supported by grants from Beijing Municipal Science and Technology (Z171100000417005 to CD) and supported in part by grant from the National Natural Science Foundation of China (81502462 to LN). CD is a Bayer Chair Professor of Tsinghua University.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Comparison of solid tumor and matched normal profiles for B7H3 expression, grouped by tissue type. (PDF 39 kb)
Supplementary information, Figure S2
Expression of B7-H3 and its receptor in HCC patients. (PDF 1004 kb)
Supplementary information, Figure S3
B7-H3 binding to CD4+, CD8+ and NK cells from tumor-bearing mice. (PDF 44 kb)
Supplementary information, Figure S4
Lack of B7-H3 enhances the immune response to E.G7 tumors. (PDF 382 kb)
Supplementary information, Figure S5
B7-H3 deficiency increased NK cell activation in B16 melanoma model. (PDF 47 kb)
Supplementary information, Figure S6
Quantification of CD107a mean fluorescence intensity on the plasma membrane of freshly isolated human NK cells. (PDF 53 kb)
Supplementary information, Data S1
Materials and Methods (PDF 116 kb)
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Lee, Yh., Martin-Orozco, N., Zheng, P. et al. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res 27, 1034–1045 (2017). https://doi.org/10.1038/cr.2017.90
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DOI: https://doi.org/10.1038/cr.2017.90
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