Department of Bioinformatics, Yale University, New Haven, CT 06520, USA.
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
Int J Mol Sci. 2021 May 25;22(11):5587. doi: 10.3390/ijms22115587.
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.
髓源性抑制细胞（MDSCs）是未成熟的髓系细胞，负责肿瘤微环境中的免疫抑制。在这里，我们报告了跨膜糖蛋白 MUC1 对 MDSC 增殖和功能活性的影响。为了确定 MUC1 在 MDSC 表型中的作用，我们分析了来自野生型（WT）和 MUC1 敲除（MUC1KO）小鼠的 MDSC，这些小鼠携带同基因胰腺（KCKO）或乳腺（C57MG）肿瘤。我们观察到与 WT 小鼠相比，MUC1KO 小鼠的胰腺和乳腺肿瘤生长增强。MUC1KO 小鼠中肿瘤生长增强与肿瘤微环境中抑制性 MDSC 和调节性 T 细胞（Tregs）数量增加有关。与 WT 宿主相比，MUC1KO 宿主显示出更高水平的 iNOS、ARG1 和 TGF-β，从而促进具有不成熟和免疫抑制表型的 MDSC 增殖。当与效应 T 细胞共培养时，与 WT 小鼠的 MDSC 相比，MUC1KO 小鼠的 MDSC 导致 T 细胞产生的 IL-2 和 IFN-γ 的抑制更高。最后，与 WT 小鼠的 MDSC 相比，MUC1KO 小鼠的 MDSC 显示出更高水平的 c-Myc 和激活的 pSTAT3，表明在 MUC1KO 宿主中 MDSC 的存活、增殖和成熟预防增加。我们报告了 KO 小鼠与 WT 小鼠相比，T 细胞功能下降。总之，数据表明 MUC1 可能调节维持 MDSC 免疫抑制特性的关键信号通路。
