title: Signaling pathways involved in MDSC regulation.
abstract: The immune system has evolved mechanisms to protect the host from the deleterious effects of inflammation. The generation of immune suppressive cells like myeloid derived suppressor cells (MDSCs) that can counteract T cell responses represents one such strategy. There is an accumulation of immature myeloid cells or MDSCs in bone marrow (BM) and lymphoid organs under pathological conditions such as cancer. MDSCs represent a population of heterogeneous myeloid cells comprising of macrophages, granulocytes and dendritic cells that are at early stages of development. Although, the precise signaling pathways and molecular mechanisms that lead to MDSC generation and expansion in cancer remains to be elucidated. It is widely believed that perturbation of signaling pathways involved during normal hematopoietic and myeloid development under pathological conditions such as tumorogenesis contributes to the development of suppressive myeloid cells. In this review we discuss the role played by key signaling pathways such as PI3K, Ras, Jak/Stat and TGFb during myeloid development and how their deregulation under pathological conditions can lead to the generation of suppressive myeloid cells or MDSCs. Targeting these pathways should help in elucidating mechanisms that lead to the expansion of MDSCs in cancer and point to methods for eliminating these cells from the tumor microenvironment.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, USA. Electronic address: prashant.trikha@osumc.edu.
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, USA; Department of Surgery, The Ohio State University, Columbus, OH 43210, USA. Electronic address: william.carson@osumc.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000502:physiology; D022423:Myeloid Cells / Q000502:physiology*; D009369:Neoplasms / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016207:Cytokines
keywords: Jak/Stat; Myeloid derived suppressor cells (MDSC); PI3K; Ras; TGFβ; Tumor microenvironment
references.citation: J Immunol. 2009 Mar 15;182(6):3801-8
references.pmid: 19265159
references.citation: Cancer Res. 2010 Jun 1;70(11):4335-45
references.pmid: 20484028
references.citation: Blood. 1996 Mar 15;87(6):2148-53
references.pmid: 8630373
references.citation: FASEB J. 2006 Sep;20(11):1921-3
references.pmid: 16877523
references.citation: Cancer Cell. 2011 Apr 12;19(4):441-55
references.pmid: 21481787
references.citation: J Immunol. 2004 Jun 15;172(12):7335-40
references.pmid: 15187109
references.citation: Eur J Cancer. 2004 Jul;40(11):1660-7
references.pmid: 15251154
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
references.pmid: 8097319
references.citation: Nature. 1987 May 28-Jun 3;327(6120):293-7
references.pmid: 3587348
references.citation: J Exp Med. 2005 Oct 17;202(8):1075-85
references.pmid: 16230475
references.citation: J Leukoc Biol. 2011 Feb;89(2):311-7
references.pmid: 21106641
references.citation: N Engl J Med. 1995 Aug 24;333(8):487-93
references.pmid: 7542747
references.citation: Immunity. 2007 Jun;26(6):726-40
references.pmid: 17582345
references.citation: Clin Cancer Res. 2008 Dec 15;14(24):8270-8
references.pmid: 19088044
references.citation: Cancer Res. 2006 Jan 15;66(2):1123-31
references.pmid: 16424049
references.citation: Stem Cells. 2010 Mar 31;28(3):620-32
references.pmid: 20073041
references.citation: Blood. 1993 Apr 1;81(7):1841-8
references.pmid: 8461470
references.citation: Cancer Res. 2007 May 1;67(9):4507-13
references.pmid: 17483367
references.citation: Nat Med. 2012 Aug;18(8):1254-61
references.pmid: 22842478
references.citation: Cancer Res. 2007 Oct 15;67(20):10019-26
references.pmid: 17942936
references.citation: J Exp Med. 2006 Nov 27;203(12):2691-702
references.pmid: 17101732
references.citation: Genes Dev. 1998 Jun 1;12(11):1610-20
references.pmid: 9620849
references.citation: Int J Biochem Cell Biol. 2010 Feb;42(2):198-201
references.pmid: 19788928
references.citation: Prostate. 2010 Mar 1;70(4):443-55
references.pmid: 19902470
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Cancer Immunol Immunother. 2008 Oct;57(10):1493-504
references.pmid: 18322683
references.citation: J Immunol. 2008 Oct 1;181(7):4666-75
references.pmid: 18802069
references.citation: J Clin Invest. 2010 Feb;120(2):457-71
references.pmid: 20093776
references.citation: Cancer Cell. 2008 Nov 4;14(5):408-19
references.pmid: 18977329
references.citation: Nature. 2000 Sep 21;407(6802):383-6
references.pmid: 11014194
references.citation: Cancer Immunol Immunother. 2011 Sep;60(9):1269-79
references.pmid: 21604071
references.citation: Immunol Rev. 2006 Oct;213:213-27
references.pmid: 16972906
references.citation: Science. 1997 Jul 18;277(5324):333-8
references.pmid: 9219684
references.citation: J Immunol. 2000 Dec 1;165(11):6024-8
references.pmid: 11086033
references.citation: Cancer Cell. 2008 Jan;13(1):23-35
references.pmid: 18167337
references.citation: J Biol Chem. 2011 Feb 11;286(6):4783-95
references.pmid: 21115501
references.citation: Immunity. 2006 Sep;25(3):487-97
references.pmid: 16949316
references.citation: Curr Biol. 2002 Jul 9;12(13):1068-75
references.pmid: 12121613
references.citation: J Endocrinol. 1996 May;149(2):249-58
references.pmid: 8708536
references.citation: PLoS One. 2011;6(11):e27690
references.pmid: 22110722
references.citation: J Immunol Methods. 2012 Jul 31;381(1-2):14-22
references.pmid: 22522114
references.citation: J Immunol. 2008 Oct 15;181(8):5791-802
references.pmid: 18832739
references.citation: J Exp Med. 2008 Sep 29;205(10):2235-49
references.pmid: 18809714
references.citation: J Immunol. 2009 May 15;182(10):6562-8
references.pmid: 19414811
references.citation: J Immunol. 2010 Aug 15;185(4):2273-84
references.pmid: 20644162
references.citation: J Exp Med. 1992 Jul 1;176(1):287-92
references.pmid: 1613462
references.citation: Cancer Res. 2001 Jun 15;61(12):4756-60
references.pmid: 11406548
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: Nat Immunol. 2003 Jun;4(6):540-5
references.pmid: 12754505
references.citation: Cancer Res. 2011 Dec 15;71(24):7463-70
references.pmid: 22025564
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83
references.pmid: 16249345
references.citation: J Clin Invest. 2013 Apr;123(4):1580-9
references.pmid: 23454751
references.citation: Growth Factors. 1996;13(3-4):251-60
references.pmid: 8919032
references.citation: J Exp Med. 1990 Dec 1;172(6):1559-70
references.pmid: 2147944
references.citation: J Biol Chem. 2001 Dec 21;276(51):48135-42
references.pmid: 11606566
references.citation: J Biol Chem. 2002 Jul 19;277(29):26293-9
references.pmid: 11978795
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6674-82
references.pmid: 18927310
references.citation: Immunity. 2002 Oct;17(4):413-23
references.pmid: 12387736
references.citation: Nat Immunol. 2013 Mar;14(3):211-20
references.pmid: 23354483
references.citation: Blood. 2004 Feb 1;103(3):1114-23
references.pmid: 14525772
references.citation: Cell. 2006 Jan 27;124(2):263-6
references.pmid: 16439202
references.citation: Nature. 2000 Mar 9;404(6774):193-7
references.pmid: 10724173
references.citation: Nature. 2009 Dec 17;462(7275):930-4
references.pmid: 20016602
references.citation: Clin Immunol. 2012 Apr;143(1):83-7
references.pmid: 22341087
references.citation: Blood. 1995 Oct 15;86(8):2948-56
references.pmid: 7579387
references.citation: Eur J Immunol. 1998 Jan;28(1):122-33
references.pmid: 9485192
references.citation: Immunity. 2012 Apr 20;36(4):503-14
references.pmid: 22520844
references.citation: Clin Cancer Res. 1996 Feb;2(2):295-302
references.pmid: 9816172
references.citation: Neuro Oncol. 2011 Jun;13(6):591-9
references.pmid: 21636707
references.citation: Trends Immunol. 2013 Feb;34(2):81-9
references.pmid: 23000011
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):2148-57
references.pmid: 19276286
references.citation: J Clin Invest. 2006 Jul;116(7):2033-43
references.pmid: 16778989
references.citation: Cancer Immunol Immunother. 2009 Jan;58(1):49-59
references.pmid: 18446337
references.citation: J Immunol. 2006 Nov 15;177(10):7303-11
references.pmid: 17082649
references.citation: J Immunol. 2003 Jan 1;170(1):270-8
references.pmid: 12496409
references.citation: Nat Rev Cancer. 2006 Mar;6(3):184-92
references.pmid: 16453012
references.citation: Cell. 2007 Jun 15;129(6):1081-95
references.pmid: 17574022
references.citation: Arthritis Rheum. 2011 Aug;63(8):2340-51
references.pmid: 21809323
references.citation: Dev Cell. 2010 Feb 16;18(2):226-36
references.pmid: 20159593
references.citation: J Clin Oncol. 2007 Jun 20;25(18):2546-53
references.pmid: 17577033
references.citation: J Cancer Res Clin Oncol. 2010 Jan;136(1):35-45
references.pmid: 19572148
references.citation: Immunity. 2008 Oct 17;29(4):565-77
references.pmid: 18848473
references.citation: Cancer Res. 2011 Aug 1;71(15):5101-10
references.pmid: 21680779
references.citation: Trends Immunol. 2002 Nov;23(11):549-55
references.pmid: 12401408
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Cancer Res. 2012 Mar 15;72(6):1363-72
references.pmid: 22287548
references.citation: J Immunol. 2005 Jan 15;174(2):636-45
references.pmid: 15634881
references.citation: Front Biosci. 2008 Jan 01;13:453-61
references.pmid: 17981560
references.citation: J Leukoc Biol. 2006 Dec;80(6):1445-53
references.pmid: 16973889
references.citation: Blood. 2010 Oct 7;116(14):2462-71
references.pmid: 20581311
references.citation: J Immunol. 2009 May 1;182(9):5693-701
references.pmid: 19380816
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2985-8
references.pmid: 7512720
references.citation: Cancer Res. 1995 Oct 15;55(20):4575-80
references.pmid: 7553632
references.citation: Blood. 2001 Mar 1;97(5):1343-51
references.pmid: 11222379
references.citation: Cell Cycle. 2013 May 1;12(9):1329-30
references.pmid: 23588070
references.citation: Scand J Immunol. 1996 May;43(5):537-44
references.pmid: 8633212
references.citation: Cell Signal. 2003 Feb;15(2):225-33
references.pmid: 12464394
references.citation: Cancer Res. 2006 Sep 15;66(18):9299-307
references.pmid: 16982775
references.citation: Cancer Cell. 2011 Apr 12;19(4):429-31
references.pmid: 21481782
references.citation: Oncoimmunology. 2013 Jul 1;2(7):e24891
references.pmid: 24073373
references.citation: Am J Pathol. 2011 Oct;179(4):2131-41
references.pmid: 21864492
references.citation: Nat Med. 2011 Mar;17(3):320-9
references.pmid: 21383745
references.citation: Eur J Immunol. 2010 Dec;40(12):3347-57
references.pmid: 21110318
references.citation: J Clin Invest. 2013 Oct;123(10):4464-78
references.pmid: 24091328
references.citation: Trends Immunol. 2002 Aug;23(8):403-8
references.pmid: 12133803
references.citation: Cancer Res. 2009 Mar 15;69(6):2506-13
references.pmid: 19244102
references.citation: Blood. 1991 Dec 1;78(11):2791-808
references.pmid: 1720034
references.citation: Circulation. 2012 Jan 17;125(2):364-74
references.pmid: 22144566
references.citation: J Immunol. 1996 Mar 1;156(5):1916-22
references.pmid: 8596044
references.citation: J Chem Biol. 2008 Nov;1(1-4):27-36
references.pmid: 19568796
references.citation: J Exp Med. 2003 Dec 1;198(11):1741-52
references.pmid: 14657224
references.citation: Med Sci (Paris). 2010 Jun-Jul;26(6-7):576-9
references.pmid: 20619155
references.citation: Cancer Res. 2005 Apr 15;65(8):3044-8
references.pmid: 15833831
references.citation: Cancer Sci. 2003 Sep;94(9):814-20
references.pmid: 12967481
references.citation: Clin Cancer Res. 1995 Jan;1(1):95-103
references.pmid: 9815891
references.citation: Immunology. 2012 Jun;136(2):176-83
references.pmid: 22304731
references.citation: Oncoimmunology. 2012 Sep 1;1(6):984-985
references.pmid: 23162780
references.citation: Immunity. 2005 Oct;23(4):361-74
references.pmid: 16226502
references.citation: J Immunol. 2012 Jun 1;188(11):5500-10
references.pmid: 22544933
references.citation: Cancer Res. 2009 Feb 15;69(4):1553-60
references.pmid: 19201693
references.citation: Cell. 2008 Aug 8;134(3):496-507
references.pmid: 18692472
references.citation: J Immunol. 2003 Feb 15;170(4):2014-21
references.pmid: 12574371
references.citation: J Biol Chem. 2005 Sep 23;280(38):33076-82
references.pmid: 16049009
references.citation: Cancer Res. 2004 Sep 1;64(17):6337-43
references.pmid: 15342423
references.citation: J Cancer Ther. 2013 May;4(3):797-803
references.pmid: 24089656
references.citation: Science. 2002 Aug 9;297(5583):1031-4
references.pmid: 12130661
references.citation: Cell. 1985 Jul;41(3):665-76
references.pmid: 2408759
references.citation: Cancer Res. 2007 Oct 1;67(19):9518-27
references.pmid: 17909062
references.citation: J Exp Med. 2005 Oct 3;202(7):931-9
references.pmid: 16186186
references.citation: J Immunol. 2001 Jan 1;166(1):678-89
references.pmid: 11123353
references.citation: J Cell Biochem. 1983;21(2):151-9
references.pmid: 6309875
references.citation: Biochem Soc Trans. 2004 Jun;32(Pt3):480-4
references.pmid: 15157166
references.citation: Cancer Cell. 2011 Apr 12;19(4):456-69
references.pmid: 21481788
references.citation: Blood. 2010 Feb 18;115(7):1461-71
references.pmid: 20008303
references.citation: J Leukoc Biol. 2012 Nov;92(5):987-97
references.pmid: 22891289
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: J Transl Med. 2011 Oct 06;9:170
references.pmid: 21978632
references.citation: J Immunol. 2011 Jan 15;186(2):697-707
references.pmid: 21148798
references.citation: Science. 2000 Feb 11;287(5455):1049-53
references.pmid: 10669418
references.citation: Annu Rev Biochem. 1987;56:779-827
references.pmid: 3304147
references.citation: Clin Cancer Res. 2008 Sep 15;14(18):5884-92
references.pmid: 18794101
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: Cell Stem Cell. 2008 Oct 9;3(4):416-28
references.pmid: 18940733
references.citation: J Leukoc Biol. 2010 Nov;88(5):839-48
references.pmid: 20587738
references.citation: Int J Cancer. 2009 Jun 1;124(11):2621-33
references.pmid: 19235923
references.citation: J Exp Med. 1993 Jan 1;177(1):237-42
references.pmid: 8418205
references.citation: Nat Med. 2005 Mar;11(3):305-11
references.pmid: 15723072
references.citation: Gastroenterology. 2008 Jul;135(1):234-43
references.pmid: 18485901
references.citation: J Clin Invest. 2008 Oct;118(10):3367-77
references.pmid: 18776941
references.citation: Nature. 1988 Jul 21;334(6179):260-2
references.pmid: 3041283
references.citation: Eur J Immunol. 1997 Jan;27(1):40-4
references.pmid: 9021996
references.citation: Nat Rev Genet. 2006 Aug;7(8):606-19
references.pmid: 16847462
references.citation: J Immunol. 2009 Jan 1;182(1):240-9
references.pmid: 19109155
references.citation: J Immunol. 1998 Nov 15;161(10):5382-90
references.pmid: 9820512
references.citation: Nat Rev Immunol. 2002 Jun;2(6):410-6
references.pmid: 12093007
references.citation: Cancer Cell. 2011 Jan 18;19(1):72-85
references.pmid: 21251614