Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models.
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing syngeneic pancreatic (KCKO) or breast (C57MG) tumors. We observed enhanced tumor growth of pancreatic and breast tumors in the MUC1KO mice compared to the WT mice. Enhanced tumor growth in the MUC1KO mice was associated with increased numbers of suppressive MDSCs and T regulatory (Tregs) cells in the tumor microenvironment. Compared to the WT host, MUC1KO host showed higher levels of iNOS, ARG1, and TGF-β, thus promoting proliferation of MDSCs with an immature and immune suppressive phenotype. When co-cultured with effector T cells, MDSCs from MUC1KO mice led to higher repression of IL-2 and IFN-γ production by T cells as compared to MDSCs from WT mice. Lastly, MDSCs from MUC1KO mice showed higher levels of c-Myc and activated pSTAT3 as compared to MDSCs from WT mice, suggesting increased survival, proliferation, and prevention of maturation of MDSCs in the MUC1KO host. We report diminished T cell function in the KO versus WT mice. In summary, the data suggest that MUC1 may regulate signaling pathways that are critical to maintain the immunosuppressive properties of MDSCs.
['Sahraei|Mahnaz|M|', 'Bose|Mukulika|M|0000-0002-2347-7413', 'Sanders|J Alexa|JA|', 'De|Chandrav|C|', 'DasRoy|Lopamudra|L|', 'Nath|Sritama|S|', 'Brouwer|Cory R|CR|', 'Mukherjee|Pinku|P|']
D000818:Animals D001943:Breast Neoplasms D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D018920:Coculture Techniques D004195:Disease Models, Animal D005260:Female D007371:Interferon-gamma D007376:Interleukin-2 D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D018396:Mucin-1 D000072737:Myeloid-Derived Suppressor Cells D010190:Pancreatic Neoplasms D016271:Proto-Oncogene Proteins c-myc D050796:STAT3 Transcription Factor D015398:Signal Transduction D013154:Spleen D050378:T-Lymphocytes, Regulatory D016212:Transforming Growth Factor beta D059016:Tumor Microenvironment
MUC1 breast cancer MDSCs Tregs iNOS immune suppression pSTAT3 TGFβ c–MYC pancreatic cancer