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.

Intermittent fasting suppressed splenic CD205+ G‐MDSC accumulation in a murine breast cancer model by attenuating cell trafficking and inducing apoptosis

“…The preparation of single-cell suspensions was described previously (Fu et al, 2020). Antibodies specific for the following surface mark- All antibodies were used at the fold dilution described on the manufacturer's recommendation.…”

“…As a result, it remains unclear whether glucose-modulating therapies would support or hinder antitumor immunity. We recently showed that CD205+ G-MDSCs, but not T cells, are sensitive to glucose deficiency (Fu et al, 2020).…”

Metabolic reprogramming of myeloid-derived suppressor cells: An innovative approach confronting challenges

“…Studies revealed that the suppressive function of MDSCs is positively correlated with glycolytic rate in solid tumor‐bearing mice models 34 . The GLUT3 hi CD205 + PMN‐MDSCs, which are particularly sensitive to glucose deprivation, showed massive accumulation in the spleen and liver of 4T1 tumor‐bearing mice 39 . Chornoguz et al 40 .…”

“… 34 The GLUT3 hi CD205 + PMN‐MDSCs, which are particularly sensitive to glucose deprivation, showed massive accumulation in the spleen and liver of 4T1 tumor‐bearing mice. 39 Chornoguz et al. 40 hypothesized that MDSCs adopt a higher rate of glycolysis to resist Fas‐ and Caspase‐mediated apoptosis, which prolong MDSCs survival in the TME.…”

“…Reducing glucose uptake by 2‐deoxy‐dglucose (2‐DG) or down‐regulating GLUT expression induce apoptosis in the MDSCs and inhibit tumor progression. 39 The ketogenic diet can lower lactate production in glycolytic tumors, resulting in fewer MDSCs and stronger antitumor immune response. 38 In addition, the proglycolytic transcription factor c‐Rel is an established therapeutic target in cancer.…”