title: Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients.
abstract: Wilms' tumor gene 1 (WT1) protein is a promising tumor-associated antigen for cancer immunotherapy. We have been performing WT1 peptide vaccination with good clinical responses in over 750 patients with leukemia or solid cancers. In this study, we generated single-cell gene-expression profiles of the effector memory (EM) subset of WT1-specific cytotoxic T lymphocytes (CTLs) in peripheral blood of nine acute myeloid leukemia patients treated with WT1 peptide vaccine, in order to discriminate responders (WT1 mRNA levels in peripheral blood decreased to undetectable levels, decreased but stayed at abnormal levels, were stable at undetectable levels, or remained unchanged from the initial abnormal levels more than 6 months after WT1 vaccination) from non-responders (leukemic blast cells and/or WT1 mRNA levels increased relative to the initial state within 6 months of WT1 vaccination) prior to WT1 vaccination. Cluster and principal component analyses performed using 83 genes did not discriminate between responders and non-responders prior to WT1 vaccination. However, these analyses revealed that EM subset of WT1-specific CTLs could be divided into two groups: the "activated" and "quiescent" states; in responders, EM subset of the CTLs shifted to the "quiescent" state, whereas in non-responders, those shifted to the "activated" state following WT1 vaccination. These results demonstrate for the first time the existence of two distinct EM states, each of which was characteristic of responders or non-responders, of WT1-specific CTLs in AML patients, and raises the possibility of using advanced gene-expression profile analysis to clearly discriminate between responders and non-responders prior to WT1 vaccination.
authors.affiliation: Departments of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nakae
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Fujiki
authors.forename: Soyoko
authors.initials: S
authors.lastname: Morimoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Kamiya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takashima
authors.forename: Jun
authors.initials: J
authors.lastname: Nakata
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Nishida
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakajima
authors.forename: Naoki
authors.initials: N
authors.lastname: Hosen
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kyo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oji
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D012333:RNA, Messenger; D022223:Vaccines, Subunit; D025721:WT1 Proteins; C583751:WT1 protein, human
references.citation: Curr Opin Immunol. 2008 Apr;20(2):211-20
references.pmid: 18502632
references.citation: Int J Med Sci. 2010 Apr 20;7(2):72-81
references.pmid: 20428337
references.citation: Mod Pathol. 2006 Jun;19(6):804-14
references.pmid: 16547468
references.citation: J Immunother. 2014 Feb-Mar;37(2):105-14
references.pmid: 24509173
references.citation: Int J Hematol. 2003 Jul;78(1):56-61
references.pmid: 12894852
references.citation: Oncologist. 2012;17(2):250-9
references.pmid: 22291091
references.citation: Anticancer Res. 2012 Mar;32(3):1081-5
references.pmid: 22399636
references.citation: Eur J Dermatol. 2012 Mar-Apr;22(2):258-9
references.pmid: 22240317
references.citation: Nature. 1990 Feb 22;343(6260):774-8
references.pmid: 2154702
references.citation: Anticancer Res. 2009 Nov;29(11):4779-84
references.pmid: 20032435
references.citation: Jpn J Clin Oncol. 2010 May;40(5):395-403
references.pmid: 20364021
references.citation: Nat Immunol. 2013 Oct;14(10):1064-72
references.pmid: 23955661
references.citation: Nat Protoc. 2012 Apr 05;7(5):829-38
references.pmid: 22481529
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13885-90
references.pmid: 15365188
references.citation: Mol Cell Biol. 1999 Mar;19(3):2289-99
references.pmid: 10022915
references.citation: Pediatr Blood Cancer. 2010 Aug;55(2):352-5
references.pmid: 20582983
references.citation: Leukemia. 2012 Mar;26(3):530-2
references.pmid: 21869838
references.citation: Methods. 2010 Apr;50(4):282-8
references.pmid: 20064613
references.citation: Nat Immunol. 2012 Oct;13(10):907-15
references.pmid: 22990888
references.citation: Brain Nerve. 2009 Jul;61(7):805-14
references.pmid: 19618858
references.citation: Front Immunol. 2013 Feb 15;4:31
references.pmid: 23424063
references.citation: Eur J Immunol. 2014 Aug;44(8):2508-20
references.pmid: 24796540
references.citation: Cell Rep. 2013 Jun 27;3(6):1945-57
references.pmid: 23746443
references.citation: Cancer Immunol Immunother. 2011 Sep;60(9):1289-97
references.pmid: 21607557
references.citation: J Cancer Res Clin Oncol. 2013 Mar;139(3):457-63
references.pmid: 23160854
references.citation: Cancer Res. 1995 Nov 15;55(22):5386-9
references.pmid: 7585606
references.citation: Oral Oncol. 2011 Jan;47(1):77-8
references.pmid: 21071262
references.citation: Clin Cancer Res. 2009 Sep 1;15(17):5323-37
references.pmid: 19723653
references.citation: Brain Tumor Pathol. 2010 Apr;27(1):29-34
references.pmid: 20425045
references.citation: Cell. 1990 Jun 29;61(7):1257-69
references.pmid: 2163761
references.citation: J Neurosurg. 2008 May;108(5):963-71
references.pmid: 18447714
references.citation: Leukemia. 2012 Jun;26(6):1410-3
references.pmid: 22157809
references.citation: Blood. 2010 Jul 15;116(2):171-9
references.pmid: 20400682
references.citation: Science. 1992 Jul 31;257(5070):674-8
references.pmid: 1323141
references.citation: Int J Hematol. 2001 Feb;73(2):177-87
references.pmid: 11372729
references.citation: Jpn J Clin Oncol. 2006 Apr;36(4):231-6
references.pmid: 16611662
references.citation: Pediatr Hematol Oncol. 2009 Jan;26(1):74-83
references.pmid: 19206012
references.citation: Int J Hematol. 2007 Dec;86(5):414-7
references.pmid: 18192109
references.citation: J Immunol. 2001 Jul 1;167(1):212-20
references.pmid: 11418651
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13824-9
references.pmid: 20631300
references.citation: Microbiol Immunol. 2004;48(3):175-84
references.pmid: 15031530
references.citation: J Biol Chem. 2012 Oct 5;287(41):34683-93
references.pmid: 22891252
references.citation: PLoS One. 2011 Mar 08;6(3):e17844
references.pmid: 21408081
references.citation: Eur J Haematol. 2010 Oct;85(4):358-60
references.pmid: 20633041
references.citation: Anticancer Res. 2011 Jul;31(7):2441-5
references.pmid: 21873157
references.citation: Nat Rev Immunol. 2012 Mar 16;12(4):306-15
references.pmid: 22421787
references.citation: Anticancer Res. 2009 May;29(5):1691-5
references.pmid: 19443388
references.citation: Int J Hematol. 2007 Jun;85(5):426-9
references.pmid: 17562620
references.citation: Methods. 2013 Jan;59(1):71-9
references.pmid: 23079396
references.citation: Jpn J Clin Oncol. 2010 May;40(5):377-87
references.pmid: 20395243
references.citation: Nat Protoc. 2011 Dec 22;7(1):118-27
references.pmid: 22193304
references.citation: J Immunol. 2002 Jun 1;168(11):5538-50
references.pmid: 12023349