title: SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1α-dependent glycolysis.
abstract: Myeloid-derived suppressor cells (MDSC) display an immature phenotype that may assume a classically activated (M1) or alternatively activated phenotype (M2) in tumors. In this study, we investigated metabolic mechanisms underlying the differentiation of MDSCs into M1 or M2 myeloid lineage and their effect on cancer pathophysiology. We found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage when cells enter the periphery from bone marrow, decreasing the suppressive function in favor of a proinflammatory M1 phenotype associated with tumor cell attack. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF-1α) pathway was required for differentiation to the M1 phenotype, which conferred protection against tumors. Our results define the essential nature of a SIRT1-mTOR/HIF-1α glycolytic pathway in determining MDSC differentiation, with implications for metabolic reprogramming as a cancer therapeutic approach.
authors.affiliation: Authors' Affiliations: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences; Institute of Radiomedicine; Biotherapy Research Center, Fudan University, Shanghai; and State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, China.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Huanrong
authors.initials: H
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.forename: Jiongbo
authors.initials: J
authors.lastname: Liao
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D006019:Glycolysis / Q000235:genetics; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008546:Melanoma, Experimental; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058570:TOR Serine-Threonine Kinases; D056564:Sirtuin 1