title: Deciphering and reversing tumor immune suppression.
abstract: Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients.
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Greg T
authors.initials: GT
authors.lastname: Motz
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D018448:Models, Immunological; D022423:Myeloid Cells / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
references.citation: Mod Pathol. 2010 Aug;23(8):1104-12
references.pmid: 20495537
references.citation: J Exp Med. 2012 Dec 17;209(13):2485-99
references.pmid: 23230000
references.citation: Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v27-8
references.pmid: 18784135
references.citation: J Immunol. 2007 Jul 1;179(1):365-71
references.pmid: 17579057
references.citation: Nat Rev Immunol. 2008 Jul;8(7):523-32
references.pmid: 18566595
references.citation: J Clin Invest. 1995 Jul;96(1):60-8
references.pmid: 7542286
references.citation: Adv Cancer Res. 2005;93:189-234
references.pmid: 15797448
references.citation: Blood. 2003 Aug 1;102(3):964-71
references.pmid: 12689940
references.citation: Immunity. 2011 Sep 23;35(3):323-35
references.pmid: 21943488
references.citation: Blood. 1999 Mar 1;93(5):1634-42
references.pmid: 10029592
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4840-8
references.pmid: 17699863
references.citation: Immunology. 2007 Jun;121(2):149-57
references.pmid: 17371541
references.citation: Science. 2002 Oct 25;298(5594):850-4
references.pmid: 12242449
references.citation: Cancer Res. 2006 Jan 15;66(2):1123-31
references.pmid: 16424049
references.citation: J Exp Med. 2001 Aug 20;194(4):481-9
references.pmid: 11514604
references.citation: J Immunol. 2000 Dec 15;165(12):7017-24
references.pmid: 11120829
references.citation: Semin Cancer Biol. 2009 Oct;19(5):298-309
references.pmid: 19482088
references.citation: Cancer Res. 2011 Aug 15;71(16):5423-34
references.pmid: 21697280
references.citation: Clin Cancer Res. 2003 Jan;9(1):84-92
references.pmid: 12538455
references.citation: Trends Mol Med. 2005 May;11(5):225-31
references.pmid: 15882610
references.citation: Nat Med. 1998 Apr;4(4):415-20
references.pmid: 9546786
references.citation: N Engl J Med. 2012 Jun 28;366(26):2455-65
references.pmid: 22658128
references.citation: J Exp Med. 2007 Jun 11;204(6):1257-65
references.pmid: 17502665
references.citation: J Clin Invest. 2009 Nov;119(11):3311-21
references.pmid: 19809157
references.citation: PLoS One. 2011;6(7):e21774
references.pmid: 21755000
references.citation: Circ Res. 2005 Feb 18;96(3):300-7
references.pmid: 15637298
references.citation: N Engl J Med. 2003 Jan 16;348(3):203-13
references.pmid: 12529460
references.citation: Science. 2006 Sep 29;313(5795):1960-4
references.pmid: 17008531
references.citation: Immunol Rev. 2009 May;229(1):114-25
references.pmid: 19426218
references.citation: Am J Physiol. 1999 Jun;276(6):H1943-50
references.pmid: 10362674
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Cancer Immunol Res. 2013 Jul;1(1):32-42
references.pmid: 24777248
references.citation: Eur J Immunol. 2003 Nov;33(11):3117-26
references.pmid: 14579280
references.citation: Am J Pathol. 2000 Nov;157(5):1703-11
references.pmid: 11073829
references.citation: Blood. 2006 Mar 1;107(5):2013-21
references.pmid: 16278308
references.citation: Cancer Metastasis Rev. 2011 Mar;30(1):141-51
references.pmid: 21298574
references.citation: Nat Rev Immunol. 2005 Jun;5(6):459-71
references.pmid: 15928678
references.citation: Immunity. 2009 May;30(5):626-35
references.pmid: 19464985
references.citation: Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):e4; author reply e5-6
references.pmid: 18216324
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7
references.pmid: 12218188
references.citation: Cancer Res. 2011 Oct 15;71(20):6391-9
references.pmid: 21900403
references.citation: Semin Cancer Biol. 2002 Feb;12(1):43-50
references.pmid: 11926411
references.citation: Blood. 2007 Jul 1;110(1):37-44
references.pmid: 17363734
references.citation: Blood. 2010 Sep 2;116(9):1454-9
references.pmid: 20498301
references.citation: Cancer Res. 2009 Apr 1;69(7):3077-85
references.pmid: 19293190
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19461-6
references.pmid: 20978210
references.citation: Semin Cancer Biol. 2012 Feb;22(1):41-9
references.pmid: 22212863
references.citation: Cancer Res. 2012 Aug 1;72(15):3735-43
references.pmid: 22593190
references.citation: Clin Cancer Res. 2012 Mar 1;18(5):1207-13
references.pmid: 22205687
references.citation: Cancer Res. 2012 May 1;72(9):2162-71
references.pmid: 22549946
references.citation: Cancer Cell. 2008 Mar;13(3):206-20
references.pmid: 18328425
references.citation: Nat Med. 2004 Sep;10(9):950-8
references.pmid: 15334073
references.citation: Cancer Res. 2003 May 15;63(10):2447-53
references.pmid: 12750265
references.citation: Clin Cancer Res. 2013 Jul 1;19(13):3439-49
references.pmid: 23649001
references.citation: Science. 2013 Mar 29;339(6127):1546-58
references.pmid: 23539594
references.citation: Hum Immunol. 2009 Jun;70(6):375-82
references.pmid: 19480853
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16813-8
references.pmid: 15548611
references.citation: Cancer Res. 2007 Feb 15;67(4):1725-34
references.pmid: 17308114
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: Clin Cancer Res. 1999 Oct;5(10):2963-70
references.pmid: 10537366
references.citation: Gynecol Oncol. 2012 Feb;124(2):192-8
references.pmid: 22040834
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: Cancer Immunol Immunother. 2010 Feb;59(2):267-77
references.pmid: 19669642
references.citation: J Exp Med. 2010 Mar 15;207(3):505-20
references.pmid: 20176801
references.citation: J Exp Med. 2001 Sep 17;194(6):823-32
references.pmid: 11560997
references.citation: J Immunol. 2007 Mar 1;178(5):2883-92
references.pmid: 17312132
references.citation: Blood. 1996 Jul 15;88(2):667-73
references.pmid: 8695814
references.citation: J Immunol. 1997 Jul 1;159(1):28-35
references.pmid: 9200435
references.citation: Mol Imaging Biol. 2009 Nov-Dec;11(6):460-6
references.pmid: 19434461
references.citation: J Exp Med. 2011 Sep 26;208(10):1949-62
references.pmid: 21930770
references.citation: Semin Immunol. 2008 Oct;20(5):286-95
references.pmid: 18951039
references.citation: Trends Mol Med. 2004 Jan;10(1):15-8
references.pmid: 14720581
references.citation: J Clin Invest. 2009 Aug;119(8):2127-30
references.pmid: 19620780
references.citation: J Immunol. 2007 Feb 1;178(3):1505-11
references.pmid: 17237399
references.citation: J Immunol. 2010 Jan 15;184(2):591-7
references.pmid: 20018619
references.citation: J Exp Med. 2005 Oct 3;202(7):919-29
references.pmid: 16186184
references.citation: Nat Rev Cancer. 2005 Apr;5(4):263-74
references.pmid: 15776005
references.citation: Cancer Res. 1999 Feb 1;59(3):720-7
references.pmid: 9973223
references.citation: Trends Pharmacol Sci. 1989 Sep;10(9):374-8
references.pmid: 2690429
references.citation: Science. 1995 Nov 10;270(5238):985-8
references.pmid: 7481803
references.citation: Cancer Immunol Immunother. 2008 Aug;57(8):1115-24
references.pmid: 18193223
references.citation: Nat Med. 2003 May;9(5):562-7
references.pmid: 12704383
references.citation: J Exp Med. 2001 Mar 5;193(5):607-20
references.pmid: 11238591
references.citation: J Exp Med. 2005 Apr 18;201(8):1257-68
references.pmid: 15824085
references.citation: Eur J Immunol. 2011 Oct;41(10):2997-3005
references.pmid: 21805470
references.citation: Nature. 2011 Jul 13;475(7355):226-30
references.pmid: 21753853
references.citation: Annu Rev Immunol. 2001;19:565-94
references.pmid: 11244047
references.citation: PLoS One. 2009 Nov 03;4(11):e7669
references.pmid: 19888452
references.citation: J Exp Med. 2000 Feb 7;191(3):411-6
references.pmid: 10662786
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15074-9
references.pmid: 10611340
references.citation: Nat Rev Immunol. 2004 Dec;4(12):941-52
references.pmid: 15573129
references.citation: Nat Rev Immunol. 2011 Sep 23;11(10):702-11
references.pmid: 21941296
references.citation: Annu Rev Immunol. 2006;24:175-208
references.pmid: 16551247
references.citation: J Exp Med. 2007 Feb 19;204(2):345-56
references.pmid: 17261634
references.citation: Clin Cancer Res. 2007 Jul 1;13(13):3951-9
references.pmid: 17606729
references.citation: Curr Opin Immunol. 2013 Apr;25(2):189-91
references.pmid: 23510648
references.citation: Immunology. 2001 Aug;103(4):449-57
references.pmid: 11529935
references.citation: Blood. 2005 Oct 1;106(7):2375-81
references.pmid: 15947091
references.citation: Nat Med. 2013 Jun;19(6):747-52
references.pmid: 23644516
references.citation: Nat Med. 2004 Sep;10(9):942-9
references.pmid: 15322536
references.citation: Trends Immunol. 2002 Sep;23(9):445-9
references.pmid: 12200066
references.citation: J Exp Med. 2008 Oct 27;205(11):2609-21
references.pmid: 18838547
references.citation: Cancer Res. 2007 Jan 1;67(1):354-61
references.pmid: 17210718
references.citation: Nat Rev Clin Oncol. 2011 Mar 01;8(4):210-21
references.pmid: 21364524
references.citation: J Biol Chem. 2002 Mar 8;277(10):8724-9
references.pmid: 11751915
references.citation: Nat Rev Cancer. 2006 Jul;6(7):521-34
references.pmid: 16794635
references.citation: J Invest Dermatol. 1998 Jul;111(1):1-6
references.pmid: 9665379
references.citation: Cancer Res. 2008 Feb 1;68(3):889-92
references.pmid: 18245491
references.citation: J Immunol. 1998 Nov 1;161(9):4842-51
references.pmid: 9794417
references.citation: Clin Cancer Res. 2003 Apr;9(4):1517-27
references.pmid: 12684428
references.citation: Cancer Res. 2013 Jun 15;73(12):3591-603
references.pmid: 23633484
references.citation: J Immunol. 2012 Nov 1;189(9):4258-65
references.pmid: 23018462
references.citation: Prostate. 2000 Jun 15;44(1):77-87
references.pmid: 10861760
references.citation: J Immunol. 2007 Sep 1;179(5):3332-41
references.pmid: 17709550
references.citation: Cancer Res. 1998 Aug 15;58(16):3491-4
references.pmid: 9721846
references.citation: Blood. 2005 Feb 15;105(4):1815-22
references.pmid: 15494428
references.citation: J Immunol. 2002 Oct 1;169(7):3581-8
references.pmid: 12244148
references.citation: Cancer Cell. 2004 Oct;6(4):409-21
references.pmid: 15488763
references.citation: Nat Immunol. 2002 Jul;3(7):611-8
references.pmid: 12087419
references.citation: Nature. 2007 Dec 6;450(7171):825-31
references.pmid: 18064003
references.citation: Cancer Res. 2006 Apr 15;66(8):4488-95
references.pmid: 16618776
references.citation: Adv Immunol. 2003;81:199-252
references.pmid: 14711057
references.citation: Cancer Res. 2003 May 1;63(9):2322-9
references.pmid: 12727857
references.citation: Nat Med. 2008 Jan;14(1):28-36
references.pmid: 18157142
references.citation: J Immunol. 2012 Nov 15;189(10):5029-36
references.pmid: 23034170
references.citation: Nat Med. 2002 Aug;8(8):793-800
references.pmid: 12091876
references.citation: J Biol Chem. 1989 Sep 5;264(25):14613-6
references.pmid: 2768235
references.citation: Cancer Res. 2012 Mar 1;72(5):1081-91
references.pmid: 22237626
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3360-5
references.pmid: 17360651
references.citation: Adv Immunol. 2000;74:181-273
references.pmid: 10605607
references.citation: Nat Immunol. 2007 Dec;8(12):1353-62
references.pmid: 17982458
references.citation: MAbs. 2012 Mar-Apr;4(2):182-97
references.pmid: 22453100
references.citation: Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4345-54
references.pmid: 17671115
references.citation: J Exp Med. 2005 Jan 17;201(2):249-57
references.pmid: 15657294
references.citation: N Engl J Med. 2011 Jun 30;364(26):2517-26
references.pmid: 21639810
references.citation: Methods Enzymol. 2009;461:3-29
references.pmid: 19480912
references.citation: Int J Cancer. 2012 Aug 1;131(3):633-40
references.pmid: 21898391
references.citation: Immunol Cell Biol. 2002 Oct;80(5):477-83
references.pmid: 12225384
references.citation: J Immunol. 2005 Feb 15;174(4):1783-6
references.pmid: 15699103
references.citation: Oncology. 2005;68(2-3):276-84
references.pmid: 16015045
references.citation: Int J Biochem Cell Biol. 2008;40(8):1443-51
references.pmid: 18325824
references.citation: J Clin Oncol. 2011 Jun 20;29(18):2493-8
references.pmid: 21576633
references.citation: J Clin Invest. 2006 Oct;116(10):2777-90
references.pmid: 17016559
references.citation: Immunity. 2009 Nov 20;31(5):787-98
references.pmid: 19879162
references.citation: Blood. 2000 Dec 1;96(12):3838-46
references.pmid: 11090068
references.citation: Cancer Res. 2012 Jul 15;72(14):3557-69
references.pmid: 22573714
references.citation: J Exp Med. 2003 Dec 15;198(12):1875-86
references.pmid: 14676299
references.citation: Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651-5
references.pmid: 1675786
references.citation: Cell Death Differ. 2007 Dec;14(12):2076-84
references.pmid: 17762882
references.citation: Cancer Res. 2005 Feb 1;65(3):1089-96
references.pmid: 15705911
references.citation: Cancer Res. 1996 Mar 1;56(5):1111-17
references.pmid: 8640769
references.citation: J Clin Invest. 2011 Dec;121(12):4746-57
references.pmid: 22056381
references.citation: Blood. 2008 Jan 1;111(1):251-9
references.pmid: 17909080
references.citation: Semin Cancer Biol. 2006 Feb;16(1):3-15
references.pmid: 16153857
references.citation: J Leukoc Biol. 2008 Dec;84(6):1472-82
references.pmid: 18725395
references.citation: Cell. 2001 Aug 10;106(3):255-8
references.pmid: 11509172
references.citation: Am J Pathol. 1997 Feb;150(2):713-25
references.pmid: 9033284
references.citation: J Immunol. 1999 Apr 15;162(8):4567-75
references.pmid: 10201996
references.citation: Gastroenterology. 1994 Oct;107(4):1050-8
references.pmid: 7523213
references.citation: Nat Med. 1996 Oct;2(10):1096-103
references.pmid: 8837607
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19055-60
references.pmid: 18025475
references.citation: Cancer Immunol Immunother. 2004 Jun;53(6):543-50
references.pmid: 14666382
references.citation: Nat Immunol. 2005 Nov;6(11):1142-51
references.pmid: 16227984
references.citation: Trends Endocrinol Metab. 2007 Dec;18(10):379-85
references.pmid: 17997104
references.citation: Nat Rev Cancer. 2008 Aug;8(8):618-31
references.pmid: 18633355
references.citation: Nat Rev Immunol. 2006 Oct;6(10):715-27
references.pmid: 16977338
references.citation: Nat Rev Cancer. 2003 Feb;3(2):110-6
references.pmid: 12563310
references.citation: Cancer Res. 2008 Sep 15;68(18):7684-91
references.pmid: 18768667
references.citation: J Immunol. 2011 Apr 15;186(8):4599-608
references.pmid: 21389258
references.citation: Blood. 2003 Jul 1;102(1):161-8
references.pmid: 12649136
references.citation: Clin Cancer Res. 2007 Dec 1;13(23):6993-7002
references.pmid: 18056175
references.citation: Breast Cancer Res Treat. 2001 Nov;70(1):65-74
references.pmid: 11767005
references.citation: J Immunol. 2011 Apr 1;186(7):4183-90
references.pmid: 21368233
references.citation: Eur J Immunol. 2008 Sep;38(9):2412-8
references.pmid: 18792019
references.citation: J Biol Chem. 2002 Aug 2;277(31):27850-5
references.pmid: 12023962
references.citation: Cancer Res. 2006 Jun 1;66(11):5716-22
references.pmid: 16740709
references.citation: Blood. 1998 Dec 15;92(12):4778-91
references.pmid: 9845545
references.citation: Nat Rev Cancer. 2009 May;9(5):361-71
references.pmid: 19343034
references.citation: J Exp Med. 2006 Apr 17;203(4):871-81
references.pmid: 16606666
references.citation: Nat Immunol. 2011 Sep 18;12(11):1096-104
references.pmid: 21926986
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):253-68
references.pmid: 22437938
references.citation: Clin Cancer Res. 2000 May;6(5):1755-66
references.pmid: 10815894