title: Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer.
abstract: NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.
authors.affiliation: Departments of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.forename: Amy
authors.initials: A
authors.lastname: Beck
authors.forename: Austin
authors.initials: A
authors.lastname: Miller
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.forename: Cheryl
authors.initials: C
authors.lastname: Eppolito
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Shashikant
authors.initials: S
authors.lastname: Lele
authors.forename: Protul
authors.initials: P
authors.lastname: Shrikant
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C104948:CTAG1B protein, human; D016207:Cytokines; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: J Immunol. 2009 May 1;182(9):5240-9
references.pmid: 19380770
references.citation: Immunology. 2005 Jun;115(2):170-8
references.pmid: 15885122
references.citation: J Immunol. 2000 Jul 1;165(1):533-8
references.pmid: 10861093
references.citation: J Immunol. 2008 Jul 1;181(1):116-25
references.pmid: 18566376
references.citation: Immunogenetics. 1997;47(1):96-8
references.pmid: 9382927
references.citation: Nat Rev Immunol. 2008 Jun;8(6):467-77
references.pmid: 18500231
references.citation: Annu Rev Immunol. 2004;22:765-87
references.pmid: 15032596
references.citation: J Immunol. 2004 May 1;172(9):5450-5
references.pmid: 15100286
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12837-42
references.pmid: 17652518
references.citation: Eur J Cancer. 2001 Sep;37(13):1709-18
references.pmid: 11527700
references.citation: Nat Immunol. 2009 Jan;10(1):29-37
references.pmid: 19043418
references.citation: Immunity. 2004 Aug;21(2):137-48
references.pmid: 15308095
references.citation: Nat Immunol. 2003 Dec;4(12):1191-8
references.pmid: 14625547
references.citation: Annu Rev Immunol. 2005;23:515-48
references.pmid: 15771580
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43
references.pmid: 16344461
references.citation: Immunity. 2008 Mar;28(3):414-24
references.pmid: 18342010
references.citation: J Virol. 2003 Apr;77(8):4911-27
references.pmid: 12663797
references.citation: PLoS One. 2008;3(10):e3409
references.pmid: 18923710
references.citation: Cancer Res. 2003 Sep 15;63(18):6076-83
references.pmid: 14522938
references.citation: Adv Exp Med Biol. 2007;590:185-93
references.pmid: 17191386
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3360-5
references.pmid: 17360651
references.citation: J Exp Med. 2006 Apr 17;203(4):871-81
references.pmid: 16606666
references.citation: J Virol. 2007 Mar;81(6):2545-53
references.pmid: 17182670