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Myeloid-restricted ablation of Shp2 restrains melanoma growth by amplifying the reciprocal promotion of CXCL9 and IFN-γ production in tumor microenvironment

Oncogene volume 37, pages 5088–5100 (2018)Cite this article

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Abstract

The Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp2) is generally considered to be an oncogene owing to its ability in enhancing the malignancy of multiple types of tumor cells; however, its role in modulating tumor immunity remains largely elusive. Here, we reported that myeloid-restricted ablation of Shp2 suppressed melanoma growth. Mechanistically, loss of Shp2 potentiates macrophage production of CXCL9 in response to IFN-γ and tumor cell-derived cytokines, thereby facilitating the tumor infiltration of IFN-γ-producing T cells that could in turn support CXCL9 production within tumor microenvironment. Collectively, our findings highlight a causative role of myeloid Shp2 in dampening T cell-mediated antitumor immunity by restraining the macrophage/CXCL9-T cell/IFN-γ feedback loop. Thus, targeting macrophage Shp2 may help to create a Th1-dominant tumor immune microenvironment.

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Acknowledgements

We thank G. Feng (University of California, San Diego, CA) for providing the Shp2flox/flox mice. This study was supported by National Natural Science Foundation of China (81702807 to P. Xiao), Key Project of the National Natural Science Foundation of China (81530001 to Y. Ke), Key Research and Development Project of Ministry of Science and Technology of China (2016FYA0501800 to Y. Ke), Natural Science Foundation of Zhejiang Province (LY16H030009 to Q. Cao), and Foundation of Health and Family Planning Commission of Zhejiang Province (2016134143 to Q. Cao).

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  1. These authors contributed equally: P. Xiao, Y. Guo.

Authors and Affiliations

  1. Department of Pathology and Pathophysiology, and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China

    P. Xiao & Q. Cao

  2. Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, 310058, Hangzhou, China

    Y. Guo, H. Zhang, X. Zhang, H. Cheng & Y. Ke

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  1. P. Xiao
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Xiao, P., Guo, Y., Zhang, H. et al. Myeloid-restricted ablation of Shp2 restrains melanoma growth by amplifying the reciprocal promotion of CXCL9 and IFN-γ production in tumor microenvironment. Oncogene 37, 5088–5100 (2018). https://doi.org/10.1038/s41388-018-0337-6

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