Zhu et al. identified a Ly6GmiLy6CloCD11b+CXCR2+ subset of MDSCs expanded in murine breast cancer tumors and in peripheral blood, and found that this cell subset promotes breast cancer metastasis to the lungs and lymph nodes in 4T1 mice by enhancing an epithelial-mesenchymal transition of tumor cells, potentially via IL-6, and by upregulating immunosuppressive checkpoint markers on CD4+ and CD8+ T cells in an IFNγ-dependent manner.
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(mi)Ly6C(lo)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 in vivo. 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-gamma. 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.
Author Info: (1) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. (2) National Key Laboratory of Medical Im
Author Info: (1) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. (2) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. (3) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. (4) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. (5) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. (6) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
