CXCR2 + MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion

Although myeloid-derived suppressor cells (MDSCs) have been demonstrated to contribute to tumor initiation, progression and metastasis, however, which MDSC subsets are preferentially expanded and activated, and what's the key molecular mechanism responsible for specific MDSC subsets in promoting tumor progression need to be fully addressed. Here we identify that Ly6G Ly6C CD11b CXCR2 subpopulation (named CXCR2 MDSCs) are predominately expanded and recruited in systemic and local tumor microenvironment during breast cancer progression and metastasis. The proportion of CXCR2 MDSCs is inversely correlated with the infiltration of CD4 or CD8 T cells. Besides, CXCR2 MDSCs promote breast cancer growth and metastasis to lung and/or lymph node . Furthermore, CXCR2 MDSCs induce epithelial mesenchymal transition (EMT) of breast cancer cells via IL-6. Moreover, CXCR2 MDSCs upregulate the expression of immunosuppressive molecules programmed cell death protein 1(PD1), PD1 ligand 1 (PDL1), lymphocyte activation gene 3 protein (LAG3), cytotoxic T lymphocyte antigen 4 (CTLA4), and T cell immunoglobulin domain and mucin domain protein 3 (TIM3) on CD4 or CD8 T cells, and induce exhaustion of the activated T cells partially via IFN-γ. These results demonstrate that CXCR2 MDSCs accelerate breast cancer progression via directly inducing cancer cell EMT and indirectly promoting T cell exhaustion, suggesting that CXCR2 MDSCs may be a potential therapeutic target of breast cancer.