Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models.

Mahnaz Sahraei,Chandrav De,J Alexa Sanders,Sritama Nath,Mukulika Bose,Lopamudra Dasroy,Cory R Brouwer,Pinku Mukherjee

doi:10.3390/ijms22115587

Abstract

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.

Highlights

A diverse population of immature myeloid cells (IMCs) make up the myeloid-derived suppressor cells (MDSCs)
2 days. n = 8 mice in each wild type (WT) and MUC1KO mice. (B) Final tumor weight in MUC1KO and WT mice injected with 106 KCKO cells. (C) For Breast Cancer model, WT and MUC1KO mice were injected subcutaneously with 106 cells and tumor burden was measured every 2 days. n = 6 and n = 7 mice in WT and MUC1KO groups respectively were used. (D) Final tumor weight in MUC1KO and WT mice injected with 106 C57MG cells
The two groups of signaling previously described to be responsible for accumulation and differentiation of MDSCs include tumor—derived growth factors (STAT3, IRF8, C/EBPβ, Notch, adenosine receptors A2b signaling, NLRP3, Rb1) and proinflammatory cytokines produced by tumor stroma (NF-κβ pathway, STAT1, STAT6, prostaglandin E2 (PGE2), COX2) [7]

Summary

Introduction

A diverse population of immature myeloid cells (IMCs) make up the myeloid-derived suppressor cells (MDSCs). This heterogenous population consists of cells (IMCs) with precursors for macrophages, granulocytes, or dendritic cells (DCs) that accumulate in chronic inflammation and tumor progression [1,2,3,4]. MDSCs express both CD11b and Gr1 markers, and are mainly of two subtypes: polymorphonuclear Ly6G+Ly6Clo (PMN) and monocytic Ly6G–Ly6Chi (M) cells. In humans, these same subtypes can be characterized as Lin-HLA-DR–/loCD33+ or Lin-HLA–DR–/loCD11b+CD14–CD15+CD33+ for PMN-MDSCs and CD14+HLA–DRneg/lo or Lin-HLA–DRneg/loCD11b+CD14+CD15- for MMDSCs [1,2,5,8,9].

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Results

Conclusion