Tumoral IL-10-activated SHP2 in macrophages promotes mammary carcinoma progression

The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is a non-receptor tyrosine phosphatase and acts as a convergent node for oncogenic cell-signaling cascades. SHP2 has been recognized as a breakthrough anti-tumor therapeutic target. However, it is still elusive for the role of SHP2 in manipulating tumor microenvironment for malignancy. Here, we found that SHP2 activation in tumor-associated macrophages (TAMs) paralleled mammary carcinoma progression. Co-culture system and human breast cancer specimens also showed high levels of phosphorylated SHP2 in macrophages. Conditional SHP2 knockout or pharmacological SHP2 inhibition blocked mammary carcinoma growth and reduced metastasis. More importantly, tumor-derived IL-10 induced SHP2 phosphorylation in macrophages upon the tumor-macrophage interaction. SHP2 activation rendered macrophages an immunosuppressive phenotype and attenuated their responsiveness to type I interferon. IL-10 deficiency in mammary carcinoma cells caused tumor regression, which was accompanied by the reduction of SHP2 activation in TAMs. These findings suggest a protumorigenic role of SHP2 in the crosstalk between macrophages and mammary carcinoma cells in tumor microenvironments and reveal that targeting SHP2 in macrophages could be a therapeutic approach to improve anticancer therapy.