title: Influence of tumors on protective anti-tumor immunity and the effects of irradiation.
abstract: Innate and adaptive immunity plays important roles in the development and progression of cancer and it is becoming apparent that tumors can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumors of patients with cancer is increased and the presence of these cells appears to present a major barrier to the induction of tumor immunity. One aspect of tumor-mediated immunoregulation which has received comparatively little attention is that which is directed toward natural killer (NK) cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating. Although the precise mechanisms underlying these localized and systemic immunoregulatory effects remain unclear, tumor-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumors to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer. This article reviews current knowledge relating to the influence of tumors on protective anti-tumor immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype, and function of innate and adaptive immune cells in patients with cancer.
authors: Department of Oncology, The Medical School, The University of Sheffield Sheffield, UK ; Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München Munich, Germany.
authors: Gemma A
authors: GA
authors: Foulds
authors: Jürgen
authors: J
authors: Radons
authors: Mira
authors: M
authors: Kreuzer
authors: Gabriele
authors: G
authors: Multhoff
authors: Alan G
authors: AG
authors: Pockley
keywords: NK cells; T cells; immunoregulation; tumor immunity; tumor microenvironment
references: Clin Cancer Res. 2008 Mar 1;14(5):1455-63
references: 18316569
references: J Innate Immun. 2011;3(4):344-54
references: 21576922
references: World J Gastroenterol. 2011 Apr 21;17(15):2019-27
references: 21528082
references: Clin Cancer Res. 2010 Mar 1;16(5):1662-72
references: 20179239
references: Radiother Oncol. 2010 Jun;95(3):350-8
references: 20430459
references: Clin Cancer Res. 2002 Mar;8(3):885-92
references: 11895923
references: Blood. 1999 Mar 1;93(5):1634-42
references: 10029592
references: Gut. 2009 May;58(5):704-20
references: 19359436
references: Crit Rev Immunol. 2007;27(1):61-95
references: 17430097
references: Cell Stress Chaperones. 1998 Mar;3(1):6-11
references: 9585177
references: Annu Rev Immunol. 2012;30:733-58
references: 22224762
references: Trends Biochem Sci. 2006 Mar;31(3):164-72
references: 16483782
references: J Exp Med. 2005 Oct 17;202(8):1075-85
references: 16230475
references: J Cell Mol Med. 2011 Apr;15(4):874-87
references: 20406322
references: Cancer Res. 2012 Jul 15;72(14):3439-44
references: 22761338
references: Clin Lymphoma. 2000 Sep;1(2):110-6; discussion 117
references: 11707818
references: Head Neck. 2013 Mar;35(3):388-98
references: 22488918
references: Int J Radiat Oncol Biol Phys. 2003 Jul 1;56(3):846-53
references: 12788194
references: Cancer Res. 1999 Jul 15;59(14):3461-7
references: 10416611
references: J Immunol. 2009 Mar 1;182(5):2753-65
references: 19234170
references: N Engl J Med. 2012 Jun 28;366(26):2455-65
references: 22658128
references: Int J Hyperthermia. 2009 May;25(3):169-75
references: 19437234
references: Clin Cancer Res. 2007 Mar 15;13(6):1757-61
references: 17363529
references: J Immunol. 2005 Sep 1;175(5):2900-12
references: 16116176
references: J Immunol. 1999 Nov 15;163(10):5211-8
references: 10553041
references: J Clin Oncol. 2009 Dec 10;27(35):5911-8
references: 19805669
references: Cell Stress Chaperones. 2001 Oct;6(4):337-44
references: 11795470
references: Science. 2011 Jan 7;331(6013):44-9
references: 21212348
references: Int Immunol. 2009 Sep;21(9):1065-77
references: 19651643
references: J Immunol. 2003 Dec 1;171(11):5931-9
references: 14634104
references: Eur J Immunol. 2005 Sep;35(9):2518-27
references: 16144035
references: Nat Rev Immunol. 2003 Mar;3(3):199-210
references: 12658268
references: Immunol Today. 1990 Jul;11(7):237-44
references: 2201309
references: J Exp Med. 2006 Jul 10;203(7):1693-700
references: 16818676
references: Immunology. 2008 Aug;124(4):445-52
references: 18540962
references: Cancer. 2010 May 1;116(9):2224-33
references: 20209608
references: Curr Drug Discov Technol. 2009 Jun;6(2):103-34
references: 19519337
references: Biomed Pharmacother. 2009 Nov;63(9):703-6
references: 19269774
references: J Immunother. 2005 Nov-Dec;28(6):593-8
references: 16224277
references: Lancet. 2003 Aug 9;362(9382):469-76
references: 12927437
references: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):733-8
references: 21187371
references: Front Oncol. 2012 Jul 25;2:75
references: 22848871
references: Lancet Oncol. 2012 Jan;13(1):e32-42
references: 22225723
references: Cancer Res. 2001 May 1;61(9):3689-97
references: 11325840
references: Cancer Immun. 2002 Feb 22;2:1
references: 12747746
references: J Exp Med. 2001 Jun 4;193(11):1295-302
references: 11390436
references: Expert Rev Anticancer Ther. 2008 Oct;8(10):1581-8
references: 18925850
references: J Immunol. 2001 May 1;166(9):5530-9
references: 11313392
references: Cancer Res. 2012 May 1;72(9):2162-71
references: 22549946
references: J Biol Chem. 2012 Apr 6;287(15):12387-94
references: 22334699
references: J Immunol. 1997 May 1;158(9):4341-50
references: 9126997
references: Nat Rev Immunol. 2002 Jun;2(6):389-400
references: 12093005
references: Int J Hyperthermia. 2009 Aug;25(5):347-54
references: 19479600
references: J Immunol. 2007 Apr 1;178(7):4089-96
references: 17371963
references: N Engl J Med. 2012 Jun 28;366(26):2443-54
references: 22658127
references: PLoS One. 2008 Apr 02;3(4):e1925
references: 18382692
references: Cancer Res. 2012 Aug 15;72(16):3967-76
references: 22700877
references: Int J Cancer. 2001 Feb 1;91(3):366-72
references: 11169961
references: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7048-53
references: 16632602
references: J Clin Invest. 2005 Dec;115(12):3623-33
references: 16308572
references: Breast Dis. 2006-2007;26:115-27
references: 17473370
references: Cell Stress Chaperones. 2010 Mar;15(2):123-41
references: 19731087
references: J Exp Med. 2001 Sep 17;194(6):823-32
references: 11560997
references: J Exp Med. 2006 Oct 2;203(10):2223-7
references: 17000870
references: J Immunol. 2007 Mar 1;178(5):2883-92
references: 17312132
references: Nat Immunol. 2005 Jun;6(6):571-8
references: 15852007
references: Eur J Immunol. 1997 Jul;27(7):1824-7
references: 9247598
references: Nature. 1992 Jul 2;358(6381):66-70
references: 1614533
references: Int J Cancer. 2007 Jul 1;121(1):95-105
references: 17315190
references: Int J Cancer. 2005 Nov 1;117(2):248-55
references: 15900607
references: Int J Cancer. 2011 Jul 15;129(2):507-12
references: 20839259
references: J Immunol. 1997 Nov 15;159(10):4772-80
references: 9366401
references: Clin Exp Immunol. 2010 Jan;159(1):93-9
references: 19817769
references: Mol Ther. 2005 Nov;12(5):789-802
references: 15925544
references: J Exp Med. 2005 Oct 3;202(7):919-29
references: 16186184
references: Nat Rev Cancer. 2005 Apr;5(4):263-74
references: 15776005
references: Clin Cancer Res. 2008 Feb 1;14(3):912-23
references: 18245555
references: Ann N Y Acad Sci. 2009 Sep;1174:99-106
references: 19769742
references: Int J Cancer. 2009 Aug 1;125(3):630-8
references: 19455675
references: J Biol Chem. 2003 Feb 28;278(9):7607-16
references: 12493773
references: Cancer Res. 1996 Nov 15;56(22):5150-5
references: 8912850
references: J Biol Chem. 1994 Aug 19;269(33):21146-54
references: 7914891
references: Cell Immunol. 2007 Nov-Dec;250(1-2):1-13
references: 18313653
references: J Immunol. 1998 Feb 1;160(3):1212-8
references: 9570536
references: Int J Cancer. 2007 Jun 15;120(12):2723-33
references: 17315189
references: Cancer Immunol Immunother. 2012 Mar;61(3):425-31
references: 22193988
references: Cancer Immun. 2010 Nov 24;10:11
references: 21090563
references: J Exp Med. 2005 May 16;201(10):1591-602
references: 15883172
references: AJR Am J Roentgenol. 2011 Dec;197(6):W992-W1000
references: 22109345
references: Nature. 2011 Jul 13;475(7355):226-30
references: 21753853
references: J Exp Med. 1993 Aug 1;178(2):597-604
references: 8340759
references: Immunology. 2013 Feb;138(2):105-15
references: 23216602
references: Curr Opin Immunol. 2003 Dec;15(6):690-6
references: 14630204
references: Nat Med. 2007 Mar;13(3):250-3
references: 17342117
references: Br J Cancer. 2004 Feb 23;90(4):926-31
references: 14970875
references: Cancer Invest. 2005;23(5):399-403
references: 16193639
references: Clin Cancer Res. 2003 Feb;9(2):606-12
references: 12576425
references: J Immunother. 2010 Nov-Dec;33(9):991-8
references: 20948437
references: J Biol Chem. 2004 Jun 25;279(26):27199-210
references: 15117956
references: Mol Ther. 2011 Sep;19(9):1737-46
references: 21673660
references: Int J Clin Pharmacol Ther. 2010 Jul;48(7):492-3
references: 20557857
references: BMC Immunol. 2012 Feb 08;13:7
references: 22316211
references: Nature. 1986 Feb 20-26;319(6055):675-8
references: 3951539
references: Immunology. 2011 May;133(1):94-104
references: 21342183
references: J Immunol Methods. 2011 Aug 31;371(1-2):8-17
references: 21723287
references: Immunity. 2011 May 27;34(5):637-50
references: 21616434
references: Nat Med. 2004 Sep;10(9):942-9
references: 15322536
references: Eur J Immunol. 2004 Mar;34(3):623-630
references: 14991591
references: Cancer Immunol Immunother. 2011 Nov;60(11):1577-86
references: 21681369
references: FASEB J. 2009 Aug;23(8):2467-77
references: 19289606
references: Radiat Res. 2010 Apr;173(4):418-25
references: 20334513
references: Target Oncol. 2012 Mar;7(1):15-28
references: 22327882
references: J Immunother. 2010 May;33(4):425-34
references: 20386464
references: Front Oncol. 2012 Sep 25;2:120
references: 23057008
references: Transplantation. 1998 Dec 27;66(12):1810-7
references: 9884280
references: Cancer Res. 1999 Jul 1;59(13):3128-33
references: 10397255
references: Cancer Immunol Immunother. 2006 Aug;55(8):891-9
references: 16187081
references: Blood. 2004 Jul 1;104(1):26-33
references: 15026316
references: Semin Cancer Biol. 2012 Aug;22(4):327-34
references: 22465232
references: Curr Opin Mol Ther. 2008 Aug;10(4):362-70
references: 18683101
references: J Exp Med. 1996 Aug 1;184(2):387-96
references: 8760792
references: Nat Med. 2007 Sep;13(9):1050-9
references: 17704786
references: Trends Immunol. 2013 Jan;34(1):33-40
references: 22999714
references: Biol Chem. 2002 Nov;383(11):1715-25
references: 12530536
references: Nature. 2007 Feb 15;445(7129):771-5
references: 17220874
references: Nature. 1997 Oct 16;389(6652):737-42
references: 9338786
references: J Immunol. 2004 Apr 1;172(7):3983-8
references: 15034008
references: J Immunol. 2001 Jun 15;166(12):7282-9
references: 11390478
references: J Leukoc Biol. 2010 Sep;88(3):445-62
references: 20445014
references: Cancer Immun. 2010 Oct 20;10:9
references: 20957980
references: Eur J Immunol. 2009 May;39(5):1323-33
references: 19337997
references: Clin Cancer Res. 2009 Apr 1;15(7):2507-13
references: 19318477
references: Int J Clin Lab Res. 1997;27(2):95-102
references: 9266279
references: J Immunol. 2011 Jun 15;186(12):6753-61
references: 21555534
references: Int J Hyperthermia. 2006 Nov;22(7):575-85
references: 17079215
references: Cancer Res. 2001 Dec 15;61(24):8643-6
references: 11751377
references: Hypertension. 2000 Aug;36(2):303-7
references: 10948094
references: Korean J Lab Med. 2011 Oct;31(4):231-7
references: 22016675
references: Eur J Immunol. 1997 Feb;27(2):563-7
references: 9045931
references: Cancer Res. 2003 Sep 15;63(18):6042-50
references: 14522933
references: Cancer Res. 2007 Sep 15;67(18):8865-73
references: 17875728
references: Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):475-81
references: 10487574
references: PLoS One. 2012;7(7):e41341
references: 22829941
references: Nat Rev Cancer. 2006 Jan;6(1):24-37
references: 16397525
references: Cancer Res. 2011 Nov 1;71(21):6621-32
references: 21937679
references: Methods. 2007 Nov;43(3):229-37
references: 17920520
references: Adv Immunol. 2011;112:137-76
references: 22118408
references: J Exp Med. 1973 Jul 1;138(1):71-88
references: 4123830
references: J Biol Chem. 1992 Aug 15;267(23):16323-9
references: 1379595
references: Nature. 2007 Feb 15;445(7129):766-70
references: 17220876
references: Lab Invest. 2002 Dec;82(12):1725-33
references: 12480922
references: J Exp Med. 1990 Jan 1;171(1):35-47
references: 2104921
references: Cancer Res. 2007 Mar 15;67(6):2840-8
references: 17363607
references: J Immunol. 1995 Apr 1;154(7):3333-40
references: 7897216
references: Methods Mol Biol. 2011;707:3-17
references: 21287325
references: Adv Cancer Res. 2001;83:117-58
references: 11665717
references: Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4345-54
references: 17671115
references: BMC Cancer. 2009 Jun 16;9:186
references: 19531227
references: Adv Immunol. 2000;74:181-273
references: 10605607
references: Gastric Cancer. 2012 Jan;15(1):27-33
references: 21626292
references: Eur J Med Res. 2011 Feb 24;16(2):57-62
references: 21463982
references: Cancer Res. 2009 Mar 15;69(6):2514-22
references: 19276342
references: Int J Cancer. 1995 Apr 10;61(2):272-9
references: 7705958
references: J Immunol. 1990 Apr 15;144(8):3238-47
references: 1691231
references: Eur J Cell Biol. 2011 Jun-Jul;90(6-7):582-92
references: 21292344
references: Front Immunol. 2012 May 04;3:95
references: 22566973
references: Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10656-61
references: 21670276
references: Neuro Oncol. 2009 Aug;11(4):394-402
references: 19028999
references: J Immunol. 2006 Jul 1;177(1):84-91
references: 16785502
references: Eur J Cancer. 2011 Mar;47(5):690-6
references: 21215610
references: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5336-41
references: 12697896
references: Radiat Environ Biophys. 2007 Mar;46(1):21-9
references: 17072632
references: Cell Stress Chaperones. 1996 Sep;1(3):167-76
references: 9222602
references: J Immunol. 2005 Dec 1;175(11):7746-54
references: 16301685
references: Cancer Immunol Immunother. 2011 Dec;60(12):1801-10
references: 21811786
references: Eur J Cell Biol. 2006 Jun;85(6):443-55
references: 16584808
references: Mol Cell Biol. 1994 Sep;14(9):5820-31
references: 7520526
references: FASEB J. 2012 Jun;26(6):2253-76
references: 22362896
references: J Immunol. 1989 Nov 15;143(10):3183-91
references: 2530273
references: Front Oncol. 2012 Jul 24;2:80
references: 22837986
references: J Immunol. 2006 Dec 1;177(11):7849-57
references: 17114456
references: J Clin Invest. 2011 Sep;121(9):3609-22
references: 21841316
references: Clin Cancer Res. 2010 Jun 1;16(11):3067-77
references: 20484020
references: J Immunol. 1995 Aug 1;155(3):1151-64
references: 7636184
references: Transplantation. 2007 Mar 27;83(6):774-82
references: 17414712
references: Blood. 1996 Apr 15;87(8):3410-7
references: 8605359
references: Cancer Res. 1996 Apr 15;56(8):1727-30
references: 8620483
references: Nat Rev Immunol. 2003 Mar;3(3):253-7
references: 12658273
references: Oncol Rep. 2003 Nov-Dec;10(6):2005-8
references: 14534734
references: Oncogene. 2003 Sep 1;22(37):5866-75
references: 12947393
references: Cell Biochem Biophys. 2011 Nov;61(2):389-92
references: 21607687
references: Semin Immunol. 2004 Apr;16(2):119-26
references: 15036235
references: J Immunol. 2007 Feb 15;178(4):2155-62
references: 17277120
references: J Biol Chem. 2010 Sep 3;285(36):27571-80
references: 20558731
references: Cell Stress Chaperones. 1999 Mar;4(1):29-35
references: 10467106
references: Cancer Immunol Immunother. 1996 Dec;43(4):226-30
references: 9003468
references: Cell Stress Chaperones. 2003 Winter;8(4):348-60
references: 15115287
references: Clin Cancer Res. 2008 Jun 15;14(12):3706-15
references: 18559587
references: Cancer Res. 2010 Jul 15;70(14):5679-85
references: 20631066
references: J Exp Med. 2006 Jul 10;203(7):1701-11
references: 16818678
references: J Immunol. 2011 Feb 15;186(4):1963-9
references: 21217015
references: Exp Gerontol. 2001 Feb;36(2):341-52
references: 11226747
references: Eur J Immunol. 2005 Jun;35(6):1678-80
references: 15902689
references: Curr Cancer Drug Targets. 2007 Jun;7(4):389-409
references: 17979632
references: Clin Cancer Res. 2007 May 15;13(10):2961-9
references: 17504997
references: Immunol Today. 1993 Oct;14(10):491-9
references: 8274189
references: Nat Immunol. 2008 May;9(5):503-10
references: 18425107
references: J Immunol. 2002 Sep 1;169(5):2756-61
references: 12193750
references: J Immunol. 2008 Sep 1;181(5):3099-107
references: 18713980
references: Biologics. 2012;6:73-82
references: 22532775
references: Eur J Immunol. 2002 Nov;32(11):3267-75
references: 12555672
references: J Exp Med. 2008 Apr 14;205(4):825-39
references: 18362171
references: Brain Res. 2001 Sep 28;914(1-2):66-73
references: 11578598
references: J Clin Invest. 2007 May;117(5):1167-74
references: 17476346
references: J Immunol. 2004 Jun 1;172(11):6539-44
references: 15153467
references: J Surg Res. 2011 Dec;171(2):637-49
references: 20828749
references: J Leukoc Biol. 2007 Jan;81(1):1-5
references: 17032697
references: Curr Opin Immunol. 1996 Oct;8(5):658-63
references: 8902391
references: Annu Rev Immunol. 2004;22:531-62
references: 15032588
references: Science. 2004 Nov 26;306(5701):1517-9
references: 15567854
references: Oncol Rep. 2006 Jul;16(1):141-6
references: 16786137
references: Science. 2005 Aug 26;309(5739):1380-4
references: 16123302
references: J Exp Med. 2001 Jun 4;193(11):1285-94
references: 11390435
references: J Mammary Gland Biol Neoplasia. 2010 Dec;15(4):411-21
references: 21161342
references: J Immunol. 2002 Jun 15;168(12):5979-83
references: 12055202
references: Cell Biochem Funct. 2012 Jan;30(1):11-7
references: 21953494
references: J Exp Med. 2006 May 15;203(5):1259-71
references: 16636135
references: Cell Stress Chaperones. 2008 Spring;13(1):1-10
references: 18347936
references: Ann Surg Oncol. 2006 Sep;13(9):1252-8
references: 16952047
references: Front Oncol. 2012 Jun 04;2:58
references: 22675673
references: Hum Immunol. 2002 Jun;63(6):444-51
references: 12039519
references: Front Oncol. 2012 Aug 24;2:102
references: 22937525
references: Eur J Immunol. 1975 Feb;5(2):112-7
references: 1234049
references: J Immunother. 2006 Jul-Aug;29(4):416-24
references: 16799337
references: J Immunol. 2005 Mar 1;174(5):2591-601
references: 15728465
references: J Clin Oncol. 2010 Jul 1;28(19):3167-75
references: 20516446
references: Curr Opin Immunol. 2012 Apr;24(2):207-12
references: 22236695
references: J Immunol. 2009 Oct 15;183(8):4921-30
references: 19801517
references: Immunol Invest. 1998 Dec;27(6):367-77
references: 9845422
references: Hum Immunol. 2012 Apr;73(4):328-34
references: 22285847
references: Biol Chem. 2003 Feb;384(2):267-79
references: 12675520
references: Lab Invest. 2007 Jun;87(6):582-90
references: 17372588
references: J Immunol. 2005 Jun 15;174(12):7516-23
references: 15944250
references: Immunol Rev. 2006 Aug;212:28-50
references: 16903904
references: Cancer Res. 1999 Oct 15;59(20):5239-44
references: 10537303