CD205+ polymorphonuclear myeloid‐derived suppressor cells suppress antitumor immunity by overexpressing GLUT3. Issue 3 (11th January 2021)

• Record Type: Journal Article
• Authors: Fu, Chenghao; Fu, Zhonglin; Jiang, Chunying; Xia, Chao; Zhang, Yiwei; Gu, Xingju; Zheng, Kexin; Zhou, Dayu; Tang, Shuang; Lyu, Shuxia; Ma, Shiliang
• Is Part Of: Cancer science. Volume 112:Issue 3(2021)
• Page Start: 1011
• Page End: 1025
• Publication Date: 2021-01-11
• Subjects: CD205 -- GLUT3 -- glycolysis -- heterogeneity -- PMN‐MDSC; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14783
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Myeloid‐derived suppressor cells (MDSCs) are responsible for antitumor immunodeficiency in tumor‐bearing hosts. Primarily, MDSCs are classified into 2 groups: monocytic (M)‐MDSCs and polymorphonuclear (PMN)‐MDSCs. In most cancers, PMN‐MDSCs (CD11b + Ly6C low Ly6G + cells) represent the most abundant MDSC subpopulation. However, the functional and phenotypic heterogeneities of PMN‐MDSC remain elusive, which delays clinical therapeutic targeting decisions. In the 4T1 murine tumor model, CD11b + Ly6G low PMN‐MDSCs were sensitive to surgical and pharmacological interventions. By comprehensively analyzing 64 myeloid cell‐related surface molecule expression profiles, cell density, nuclear morphology, and immunosuppressive activity, the PMN‐MDSC population was further classified as CD11b + Ly6G low CD205 + and CD11b + Ly6G high TLR2 + subpopulations. The dichotomy of PMN‐MDSCs based on CD205 and TLR2 is observed in 4T07 murine tumor models (but not in EMT6). Furthermore, CD11b + Ly6G low CD205 + cells massively accumulated at the spleen and liver of tumor‐bearing mice, and their abundance correlated with in situ tumor burdens (with or without intervention). Moreover, we demonstrated that CD11b + Ly6G low CD205 + cells were sensitive to glucose deficiency and 2‐deoxy‐d ‐glucose (2DG) treatment. Glucose transporter 3 (GLUT3) knockdown by siRNA significantly triggered apoptosis and reduced glucose uptake in CD11b + Ly6G low CD205 + cells, demonstrating the dependence of CD205 + PMN‐MDSCs survival on both glucose uptake and GLUT3 overexpression. As GLUT3 has been recognized as a target for the rescue of host antitumor immunity, our results further directed the PMN‐MDSC subsets into the CD205 + GLUT3 + subpopulation as future targeting therapy. Abstract : We confirmed that CD205+ PMN‐MDSCs were potent immunosuppressive cells in vitro as well as in vivo and sensitive to glucose deficiency and 2‐deoxy‐D‐glucose (2DG) treatment in vitro. GLUT3 knockdown by siRNA significantly reduced the survival and glucose uptake rate of CD205+ PMN‐MDSCs and markedly retarded transplanted 4T1 tumor growth. Our results implications that PMN‐MDSC subsets in peripheral organs are also phenotypically and functionally heterogeneous, and glucose metabolism patterns profoundly affected the anti‐tumor immunity.