Natural immunity to pluripotency antigen OCT4 in humans.
OCT4 is a transcription factor critical for the pluripotency of human embryonal stem (ES) and induced pluipotency stem (IPS) cells. OCT4 is commonly expressed in germ-cell tumors as well as putative cancer stem cells in several tumors, and is a key determinant of oncogenic fate in germ-cell tumors. The capacity of the human immune system to recognize this critical stem-cell gene is not known, but has implications for preventing tumors with ES/IPS-based therapies and targeting stem-cell pathways in cancer. Here we show that OCT4-specific T cells can be readily detected in freshly isolated T cells from most (>80%) healthy donors. The reactivity to OCT4-derived peptides resides primarily in the CD45RO(+) memory T-cell compartment and consists predominantly of CD4(+) T cells. T cells reactive against OCT4-derived peptides can be readily expanded in culture using peptide-loaded dendritic cells. In contrast to healthy donors, immunity to OCT4 was detected in only 35% of patients with newly diagnosed germ-cell tumors. However, chemotherapy of germ-cell tumors led to the induction of anti-OCT4 immunity in vivo in patients lacking such responses at baseline. These data demonstrate the surprising lack of immune tolerance to this critical pluripotency antigen in humans. Harnessing natural immunity to this antigen may allow immune-based targeting of pluripotency-related pathways for prevention of cancers, including those in the setting of ES/IPS-based therapies.
Dhodapkar
Kavita M
KM
Department of Pediatrics, Yale University, New Haven, CT 06510, USA. kavita.dhodapkar@yale.edu
Feldman
Darren
D
Matthews
Phillip
P
Radfar
Soroosh
S
Pickering
Roxana
R
Turkula
Stefan
S
Zebroski
Henry
H
Dhodapkar
Madhav V
MV
D000941:Antigens / Q000276:immunology*; D001782:Blood Donors; D049109:Cell Proliferation; D002469:Cell Separation; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D009373:Neoplasms, Germ Cell and Embryonal / Q000276:immunology / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000276:immunology*; D039904:Pluripotent Stem Cells / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D000941:Antigens; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human
Nat Rev Immunol. 2008 Jan;8(1):59-73
18097448
Stem Cells. 2009 May;27(5):1050-6
19415771
Cell Stem Cell. 2007 Oct 11;1(4):403-15
18159219
Biochem Biophys Res Commun. 2009 May 29;383(2):157-62
19268426
Eur J Cancer. 1993;29A(13):1895-9
8260249
J Exp Med. 1999 Sep 6;190(5):705-15
10477554
Nature. 2009 Aug 27;460(7259):1085-6
19713919
Biol Chem. 2009 Oct;390(10):1003-12
19642878
J Immunol. 2007 Nov 1;179(9):5785-92
17947651
Crit Rev Oncog. 2006 Dec;12(3-4):171-203
17425502
Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4528-37
17671139
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14010-5
19666607
Stem Cell Rev. 2007 Jan;3(1):49-59
17873381
Nat Biotechnol. 2009 Aug;27(8):743-5
19590502
Cell. 2005 Sep 23;122(6):947-56
16153702
Curr Opin Immunol. 2010 Apr;22(2):245-50
20144857
Cell Stem Cell. 2008 Apr 10;2(4):297-9
18397746
Curr HIV/AIDS Rep. 2005 Aug;2(3):146-53
16091262
Curr Stem Cell Res Ther. 2009 Jan;4(1):70-80
19149632
Nature. 2009 Aug 27;460(7259):1145-8
19668190
J Exp Med. 2007 Apr 16;204(4):831-40
17389240
J Exp Med. 2002 Jan 7;195(1):125-33
11781371
Immunity. 2005 Mar;22(3):371-83
15780993
Leukemia. 2009 Nov;23(11):2042-51
19641521
Stem Cells. 2009 Dec;27(12):3103-11
19816950
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8633-8
10411927
Nat Rev Cancer. 2003 Jul;3(7):517-25
12835671
Cancer Cell. 2003 Nov;4(5):361-70
14667503
Nature. 2001 Nov 1;414(6859):105-11
11689955
Nat Genet. 2008 May;40(5):499-507
18443585
Cell. 2009 Apr 3;137(1):13-7
19345179
Int J Cancer. 2006 Dec 15;119(12):2851-60
16998881
Cell. 2007 Nov 30;131(5):861-72
18035408
Exp Mol Pathol. 2009 Jun;86(3):192-7
19171137
Curr Opin Immunol. 1998 Oct;10(5):588-94
9794842
PLoS One. 2009 Nov 30;4(11):e8065
19956629
Nat Rev Immunol. 2006 Oct;6(10):715-27
16977338
J Clin Oncol. 2008 Jun 10;26(17):2846-53
18539963