Myeloid Specific Shp2 Contributes To Tumor Immune Escape Via Suppressing CXCL9/IFN-? Feedback

The immunosuppressive nature of tumor microenvironment is the most responsible factors for the failure of anti-tumor immune response.One of its prominent features is the impaired intratumor infiltration of CD8~+cytotoxic T lymphocytes due to lacking T cell-attracting chemokines.As an important participant in shaping the tumor microenvironment,tumor-associated macrophages(TAMs)mediate tumor angiogenesis and immune evasion.Thus,TAMs are expected to become an important target in anti-tumor immunotherapy.Finding the elements that regulate TAMs function is of great significance for shaping the anti-tumor immune microenvironment and promoting tumor immunotherapy.The Src homology 2 domain-containing protein tyrosine phosphatase 2(Shp2)is a classic oncogene in multiple types of cancers and highly expressed in lung cancer tissues.Recently,the development of Shp2 allosteric inhibitors has become a hot spot in targeted drugs of lung cancer.However,although previous studies reveal roles of Shp2 in tumor cells extensively,current understanding towards its role in tumor immunity remains largely limited,despite that Shp2 is also highly expressed in macrophages.In addition,In our study,we first reported the critical role of Shp2 in promoting tumor immune evasion.Myeloid-restricted ablation of Shp2 suppressed melanoma growth,and the impaired growth of melanoma in Shp2 deletion mice is associated with the increased percentage of tumor-infiltrating CD8~+T cells.Mechanistically,loss of Shp2 enhances the production of CXCL9 in macrophages in response to IFN-?and tumor cell-derived cytokines,thereby promoting the intratumor infiltration of CD8~+T cells and Th1 cells,which further increasing the level of IFN-?in tumor microenvironment.The positive correlation between CXCL9 and IFN-?was further confirmed by analyzing clinical patient samples of 11 types of tumors in the GEO database.Collectively,Shp2 deficiency in macrophages amplifies the intratumoral macrophage/CXCL9-T cell/IFN-?feedback loop,and is helpful for creating a Th1-dominant tumor immune microenvironment.