Regulation of cancer germline antigen gene expression: implications for cancer immunotherapy.
Cancer germline (CG; also known as cancer-testis) antigen genes are normally expressed in germ cells and trophoblast tissues and are aberrantly expressed in a variety of human malignancies. CG antigen genes have high clinical relevance as they encode a class of immunogenic and highly selective tumor antigens. CG antigen-directed immunotherapy is undergoing clinical evaluation for the treatment of a number of solid tumor malignancies and has been demonstrated to be safe, provoke immune responses and be of therapeutic benefit. Achieving an improved understanding of the mechanisms of CG antigen gene regulation will facilitate the continued development of targeted therapeutic approaches against tumors expressing these antigens. Substantial evidence suggests epigenetic mechanisms, particularly DNA methylation, as a primary regulator of CG antigen gene expression in normal and cancer cells as well as in stem cells. The roles of sequence-specific transcription factors and signal transduction pathways in controlling CG antigen gene expression are less clear but are emerging. A combinatorial therapeutic approach involving epigenetic modulatory drugs and CG antigen immunotherapy is suggested based on these data and is being actively pursued. In this article, we review the mechanisms of CG antigen gene regulation and discuss the implications of these mechanisms for the development of cancer immunotherapy approaches targeting CG antigens.
Akers
Stacey N
SN
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Odunsi
Kunle
K
Karpf
Adam R
AR
D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000628:therapy
D000951:Antigens, Neoplasm
Clin Cancer Res. 2004 Feb 1;10(3):890-6
14871964
Clin Cancer Res. 2006 Oct 1;12(19):5777-85
17020984
J Cell Physiol. 2006 Apr;207(1):58-66
16252259
Eur J Clin Invest. 2005 Jun;35(6):380-7
15948899
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4760-5
10781081
Immunogenetics. 1995;42(4):282-90
7672823
Immunol Rev. 2002 Oct;188:22-32
12445278
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20422-7
19088187
Cancer Res. 2004 Sep 1;64(17):5988-93
15342378
Genes Dev. 2002 Jul 15;16(14):1779-91
12130538
J Clin Oncol. 2005 Apr 1;23(10):2346-57
15800326
J Invest Dermatol. 2007 Sep;127(9):2123-8
17495964
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10697-702
15252201
Stem Cells. 2009 Apr;27(4):822-4
19350682
Cancer Res. 2005 Sep 1;65(17):7763-74
16140944
Nature. 2004 May 27;429(6990):457-63
15164071
Nat Rev Cancer. 2005 Aug;5(8):615-25
16034368
Int J Cancer. 2008 Feb 15;122(4):777-84
17957795
Oncogene. 2001 May 28;20(24):3139-55
11420731
Science. 2001 Aug 10;293(5532):1074-80
11498575
PLoS One. 2009;4(3):e4961
19305507
Clin Cancer Res. 2008 Jun 1;14(11):3283-90
18519754
Epigenomics. 2009 Oct;1(1):153-61
22122641
Oncogene. 2002 Aug 12;21(35):5400-13
12154403
J Immunol. 1999 Nov 15;163(10):5211-8
10553041
Hum Reprod. 2007 Apr;22(4):953-60
17208940
PLoS One. 2009 Dec 04;4(12):e8189
19997593
Curr Opin Genet Dev. 2006 Apr;16(2):137-42
16503130
Mol Cancer Res. 2009 Jun;7(6):851-62
19531572
Blood. 2003 Jun 1;101(11):4644-6; discussion 4645-6
12756166
Cancer Res. 2000 Sep 1;60(17):4946-52
10987311
Mol Cancer. 2007 Feb 02;6:12
17274819
Oncogene. 2003 Sep 29;22(42):6484-8
14528272
J Cell Sci. 2003 Jun 1;116(Pt 11):2117-24
12730288
J Clin Oncol. 2002 Mar 15;20(6):1692-703
11896121
Mol Hum Reprod. 2008 Feb;14(2):107-16
18048459
Mol Cancer Res. 2006 May;4(5):339-49
16687489
Am J Pathol. 2009 Jul;175(1):314-23
19498007
FEBS Lett. 2009 Jun 5;583(11):1713-20
19376112
Nucleic Acids Res. 2007;35(21):7372-88
17962299
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11160-5
16847267
Mol Cell Biol. 2003 Mar;23(6):1946-60
12612069
J Biol Chem. 2006 Apr 14;281(15):10118-26
16497664
Mol Carcinog. 2010 Jun;49(6):532-44
20082319
Mol Cancer Res. 2009 Apr;7(4):523-35
19372581
Clin Cancer Res. 2009 Sep 1;15(17):5323-37
19723653
Cancer Immun. 2003 Dec 18;3:19
14680360
Biochem Pharmacol. 2006 Nov 30;72(11):1577-88
16854382
Cancer Res. 2005 Sep 1;65(17):7751-62
16140943
Mol Cancer Ther. 2009 Dec;8(12):3191-202
19934278
Cancer Res. 2005 Mar 15;65(6):2207-15
15781633
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1914-8
9050879
J Immunother. 2001 Mar-Apr;24(2):151-61
11265773
EMBO J. 2008 Oct 22;27(20):2681-90
18818694
Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R47-58
15809273
J Exp Med. 1998 Jan 19;187(2):265-70
9432985
Nat Immunol. 2000 Dec;1(6):515-20
11101874
Cancer Immunol Immunother. 2009 Apr;58(4):589-601
18791715
Cancer J. 2000 May;6 Suppl 3:S250-8
10874495
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10067-71
9707601
J Exp Med. 1998 Apr 20;187(8):1349-54
9547346
Oncogene. 2002 Aug 12;21(35):5496-503
12154410
Mol Cancer Ther. 2009 Jun;8(6):1409-20
19509247
Nat Rev Cancer. 2005 May;5(5):397-405
15864281
Mol Cancer Res. 2007 Jul;5(7):749-59
17634428
Clin Cancer Res. 2007 Jun 1;13(11):3333-8
17545540
J Cell Physiol. 2008 May;215(2):287-91
18205182
Science. 1991 Dec 13;254(5038):1643-7
1840703
Oncogene. 2007 Jun 28;26(30):4394-403
17260018
Cancer Immunol Immunother. 2009 Mar;58(3):383-94
18677478
Epigenetics. 2008 Jan-Feb;3(1):38-42
18094622
Semin Cancer Biol. 2002 Oct;12(5):399-414
12191639
Int J Cancer. 1996 Nov 15;68(4):464-70
8945617
Cancer Res. 2002 Jul 1;62(13):3630-5
12097265
Cancer Res. 2003 Sep 15;63(18):6076-83
14522938
Cancer Res. 1994 Apr 1;54(7):1766-71
7511051
Nucleic Acids Res. 2009 Jan;37(Database issue):D816-9
18838390
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7149-53
8692960
Adv Immunol. 2000;74:181-273
10605607
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6806-11
12011441
Curr Opin Immunol. 1997 Oct;9(5):702-8
9368780
Mol Pharmacol. 2004 Jan;65(1):18-27
14722233
Genes Dev. 2009 Apr 1;23(7):781-3
19339683
Mol Cell Biol. 2008 Nov;28(21):6720-9
18765639
Cancer Immun. 2007 Dec 21;7:21
18095639
Cancer Res. 2007 Oct 15;67(20):9954-62
17942928
Clin Cancer Res. 2007 Aug 15;13(16):4713-20
17699848
Epigenetics. 2006 Jul-Sep;1(3):116-20
17786175
Science. 2006 Oct 6;314(5796):126-9
16946036
Cancer Res. 2001 Jul 15;61(14):5544-51
11454705
Cancer Immunol Immunother. 2009 Oct;58(10):1635-46
19221743
Genes Dev. 2005 Apr 1;19(7):815-26
15774718
J Exp Med. 2000 Feb 21;191(4):625-30
10684854
Curr Opin Immunol. 2004 Apr;16(2):157-62
15023407
Cancer Immun. 2004 Jan 23;4:1
14738373
Stem Cells. 2007 Mar;25(3):707-11
17138959
J Immunol. 2000 Jul 15;165(2):1153-9
10878395
Gynecol Oncol. 2010 Feb;116(2):195-201
19854495
Clin Cancer Res. 2008 Apr 1;14(7):1984-96
18381936
Oncogene. 2006 Nov 2;25(52):6975-85
16715135
J Clin Oncol. 2007 Jul 10;25(20):2884-93
17617519
EMBO J. 2008 Oct 22;27(20):2691-701
18818693
Mol Cell Biol. 1999 Nov;19(11):7327-35
10523621
Nat Med. 2003 Oct;9(10):1269-74
14502282
Cancer Res. 2004 Dec 15;64(24):9167-71
15604288