CD205+ polymorphonuclear myeloid-derived suppressor cells suppress antitumor immunity by overexpressing GLUT3.

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+Ly6ClowLy6G+ 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+Ly6Glow 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+Ly6GlowCD205+ and CD11b+Ly6GhighTLR2+ subpopulations. The dichotomy of PMN‐MDSCs based on CD205 and TLR2 is observed in 4T07 murine tumor models (but not in EMT6). Furthermore, CD11b+Ly6GlowCD205+ 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+Ly6GlowCD205+ 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+Ly6GlowCD205+ 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.