title: mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors.
abstract: CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) play critical roles in controlling the processes of tumors, infections, autoimmunity and graft rejection. Immunosuppressive drug rapamycin (RPM), targeting on the key cellular metabolism molecule mTOR, is currently used in clinics to treat patients with allo-grafts, autoimmune diseases and tumors. However, the effect of RPM on MDSCs has not been studied. RPM significantly decreases the cell number and the immunosuppressive ability on T cells of CD11b(+) Ly6C(high) monocytic MDSCs (M-MDSCs) in both allo-grafts-transplanted and tumor-bearing mice respectively. Mice with a myeloid-specific deletion of mTOR have poor M-MDSCs after grafting with allo-skin tissue or a tumor. Grafting of allo-skin or tumors significantly activates glycolysis pathways in myeloid precursor cells in bone marrow, which is inhibited by RPM or mTOR deletion. 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway, inhibits M-MDSC differentiation from precursors, while enhancing glycolysis by metformin significantly rescues the RPM-caused deficiency of M-MDSCs. Therefore, we offer evidence supporting that mTOR is an intrinsic factor essential for the differentiation and immunosuppressive function of M-MDSCs and that these metabolism-relevant medicines may impact MDSCs-mediated immunosuppression or immune tolerance induction, which is of considerable clinical importance in treating graft rejection, autoimmune diseases and cancers.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, Peking University Third Hospital, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|Department of Oncology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Oncology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Wang
authors.affiliation: Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Peking University Third Hospital, Beijing, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D064591:Allografts; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D007165:Immunosuppression Therapy; D051379:Mice; D018345:Mice, Knockout; D000072737:Myeloid-Derived Suppressor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D052247:Nitric Oxide Synthase Type II; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
references.citation: Clin Immunol. 2003 Feb;106(2):148-54
references.pmid: 12672405
references.citation: Immunity. 2008 Oct 17;29(4):565-77
references.pmid: 18848473
references.citation: Transpl Immunol. 2007 Apr;17(3):153-61
references.pmid: 17331841
references.citation: Nat Med. 2007 Jul;13(7):828-35
references.pmid: 17603493
references.citation: Transpl Immunol. 2012 Aug;27(1):30-8
references.pmid: 22613676
references.citation: EMBO J. 2007 Jan 24;26(2):505-15
references.pmid: 17245434
references.citation: J Immunol. 2009 Jan 1;182(1):240-9
references.pmid: 19109155
references.citation: Am J Transplant. 2009 Sep;9(9):2034-47
references.pmid: 19681826
references.citation: Cancer Res. 2014 Sep 1;74(17):4762-71
references.pmid: 25023728
references.citation: Nat Commun. 2014;5:4696
references.pmid: 25175012
references.citation: Mol Cancer Ther. 2011 Dec;10(12):2350-62
references.pmid: 21992792
references.citation: J Immunol. 2009 May 15;182(10):6562-8
references.pmid: 19414811
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2497-506
references.pmid: 18375721
references.citation: Blood. 2012 Aug 16;120(7):1422-31
references.pmid: 22786879
references.citation: Nat Rev Endocrinol. 2014 Mar;10(3):143-56
references.pmid: 24393785
references.citation: Biochem Biophys Res Commun. 1967 Nov 17;29(3):444-9
references.pmid: 6076246
references.citation: Mol Cell. 2006 Apr 21;22(2):159-68
references.pmid: 16603397
references.citation: Curr Opin Immunol. 2011 Oct;23(5):692-7
references.pmid: 21802931
references.citation: J Immunol. 2011 Sep 1;187(5):2329-35
references.pmid: 21813777
references.citation: J Immunol. 2012 Nov 15;189(10):4989-5000
references.pmid: 23045614
references.citation: JAMA. 2014 Dec 24-31;312(24):2668-75
references.pmid: 25536258
references.citation: Am J Transplant. 2010 Dec;10(12):2604-14
references.pmid: 21114641
references.citation: Am J Transplant. 2014 Sep;14(9):2106-19
references.pmid: 25088685
references.citation: J Immunol. 2001 Jan 1;166(1):678-89
references.pmid: 11123353
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: Blood. 2008 Apr 15;111(8):4233-44
references.pmid: 18272812
references.citation: J Clin Invest. 2001 Oct;108(8):1167-74
references.pmid: 11602624
references.citation: Annu Rev Pharmacol Toxicol. 2012;52:381-400
references.pmid: 22017684
references.citation: Blood. 2011 Apr 21;117(16):4273-83
references.pmid: 21368289
references.citation: Transplantation. 2008 Oct 27;86(8):1125-34
references.pmid: 18946352
references.citation: Cell. 2006 Oct 6;127(1):125-37
references.pmid: 16962653
references.citation: J Immunol. 2008 Oct 15;181(8):5791-802
references.pmid: 18832739
references.citation: Diabetes. 2015 Jun;64(6):2028-41
references.pmid: 25552600
references.citation: FEBS J. 2011 Jan;278(1):85-96
references.pmid: 21114628
references.citation: Immunity. 2010 Jun 25;32(6):790-802
references.pmid: 20605485
references.citation: Oncogene. 2013 Mar 21;32(12):1475-87
references.pmid: 22665053
references.citation: J Immunol. 2014 Jul 1;193(1):130-8
references.pmid: 24907345
references.citation: Immunol Rev. 2012 Sep;249(1):43-58
references.pmid: 22889214
references.citation: Am J Physiol Renal Physiol. 2012 Aug 15;303(4):F569-75
references.pmid: 22696604
references.citation: J Immunol. 2008 Jun 15;180(12):7898-906
references.pmid: 18523253
references.citation: Blood. 2011 Nov 17;118(20):5498-505
references.pmid: 21972293
references.citation: J Immunol. 2002 Jan 15;168(2):689-95
references.pmid: 11777962
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Curr Opin Oncol. 2012 Nov;24(6):623-34
references.pmid: 22960556
references.citation: J Gen Physiol. 1927 Mar 7;8(6):519-30
references.pmid: 19872213
references.citation: J Immunol. 2010 Oct 1;185(7):3919-31
references.pmid: 20805416
references.citation: Curr Biol. 2006 Sep 19;16(18):1865-70
references.pmid: 16919458
references.citation: Nature. 2005 Oct 13;437(7061):1032-7
references.pmid: 16136080
references.citation: Br J Pharmacol. 1989 Feb;96(2):418-24
references.pmid: 2924084
references.citation: Trends Immunol. 2011 Jan;32(1):19-25
references.pmid: 21067974
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10574-9
references.pmid: 25002509
references.citation: Cell Mol Immunol. 2010 Nov;7(6):419-27
references.pmid: 20871628
references.citation: Cancer Cell. 2008 Jan;13(1):23-35
references.pmid: 18167337
references.citation: FASEB J. 2013 Oct;27(10):3979-90
references.pmid: 23882125
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4894-903
references.pmid: 24282297
references.citation: Cancer Treat Rev. 2014 Sep;40(8):980-9
references.pmid: 25037117
references.citation: Blood. 2000 Jan 1;95(1):212-20
references.pmid: 10607705
references.citation: Curr Opin Immunol. 2010 Apr;22(2):238-44
references.pmid: 20171075
references.citation: Am J Transplant. 2009 Dec;9(12):2655-61
references.pmid: 19788500
references.citation: Expert Rev Clin Immunol. 2014 Oct;10(10):1385-94
references.pmid: 25119260
references.citation: Diabetes Obes Metab. 2005 Nov;7(6):654-65
references.pmid: 16219009