Spontaneous antibody, and CD4 and CD8 T-cell responses against XAGE-1b (GAGED2a) in non-small cell lung cancer patients
Yoshihiro Ohue
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorShingo Eikawa
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorNami Okazaki
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorYu Mizote
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorMidori Isobe
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorAkiko Uenaka
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorMinoru Fukuda
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorLloyd J. Old
Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York
Search for more papers by this authorMikio Oka
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorCorresponding Author
Eiichi Nakayama
Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan
Tel.: +81-86-462-1111ext54954, Fax: +81-86-464-1109
Faculty of Health and Welfare, Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki, Okayama 701-0193, JapanSearch for more papers by this authorYoshihiro Ohue
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorShingo Eikawa
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorNami Okazaki
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorYu Mizote
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorMidori Isobe
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorAkiko Uenaka
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorMinoru Fukuda
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorLloyd J. Old
Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York
Search for more papers by this authorMikio Oka
Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan
Search for more papers by this authorCorresponding Author
Eiichi Nakayama
Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan
Tel.: +81-86-462-1111ext54954, Fax: +81-86-464-1109
Faculty of Health and Welfare, Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki, Okayama 701-0193, JapanSearch for more papers by this authorAbstract
The spontaneous immune responses against XAGE-1b (GAGED2a) were analyzed in non-small cell lung cancer (NSCLC) patients. An antibody response against XAGE-1b (GAGED2a) was observed in 10% (20/200) of NSCLC patients and in 19% (13/69) of stage IIIB/IV lung adenocarcinoma patients. A CD4 T-cell response was detected in 88% (14/16) and a CD8 T-cell response in 67% (6/9) in the XAGE-1b (GAGED2a) antibody-positive patients examined. Frequent antibody responses and CD4 and CD8 T-cell responses in XAGE-1b (GAGED2a) antibody-positive patients indicate the strong immunogenicity of the XAGE-1b (GAGED2a) antigen in NSCLC patients. We established T-cell clones from PBMCs of antibody-positive patients and determined the DRB1*04:05-restricted XAGE-1b (GAGED2a) 18–31 peptide (14-mer) as a CD4 T cell epitope and the A*02:06-restricted XAGE-1b (GAGED2a) 21-29 peptide (9-mer) as a CD8 T cell epitope. As for peptide recognition, CD4 and CD8 T-cell clones responded to naturally processed antigen. The CD4 T-cell clone recognized DCs pulsed with the synthetic protein or a lysate from XAGE-1b-transfected 293T cells. The CD8 T-cell clone showed cytotoxicity against a tumor expressing XAGE-1b (GAGED2a) and the appropriate HLA class I allele. These findings establish XAGE-1b (GAGED2a) as a promising target for a lung cancer vaccine.
References
- 1 Old LJ, Chen YT. New paths in human cancer serology. J Exp Med 1998; 187: 1163–67.
- 2 Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 2005; 5: 615–25.
- 3 Hofmann O, Caballero OL, Stevenson BJ, Chen YT, Cohen T, Chua R, Maher CA, Panji S, Schaefer U, Kruger A, Lehvaslaiho M, Carninci P, et al. Genome-wide analysis of cancer/testis gene expression. Proc Natl Acad Sci U S A 2008; 105: 20422–27.
- 4 Jäger E, Chen YT, Drijfhout JW, Karbach J, Ringhoffer M, Jäger D, Arand M, Wada H, Noguchi Y, Stockert E, Old LJ, Knuth A. Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 1998; 187: 265–70.
- 5 Gnjatic S, Wheeler C, Ebner M, Ritter E, Murray A, Altorki NK, Ferrara CA, Hepburne-Scott H, Joyce S, Koopman J, McAndrew MB, Workman N, et al. Seromic analysis of antibody responses in non-small cell lung cancer patients and healthy donors using conformational protein arrays. J Immunol Methods 2009; 341: 50–58.
- 6 Rosenberg SA. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 1999; 10: 281–87.
- 7 Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 2002; 188: 22–32.
- 8 Old LJ. Cancer vaccines: an overview. Cancer Immun 2008; 8( Suppl 1): 1.
- 9 Caballero OL, Chen YT. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 2009; 100: 2014–21.
- 10 Brinkmann U, Vasmatzis G, Lee B, Pastan I. Novel genes in the PAGE and GAGE family of tumor antigens found by homology walking in the dbEST database. Cancer Res 1999; 59: 1445–48.
- 11 Brinkmann U, Vasmatzis G, Lee B, Yerushalmi N, Essand M, Pastan I. PAGE-1, an X chromosome-linked GAGE-like gene that is expressed in normal and neoplastic prostate, testis, and uterus. Proc Natl Acad Sci U S A 1998; 95: 10757–62.
- 12 Liu XF, Helman LJ, Yeung C, Bera TK, Lee B, Pastan I. XAGE-1, a new gene that is frequently expressed in Ewing's sarcoma. Cancer Res 2000; 60: 4752–55.
- 13Vega Genome Browser. Available at: http://vega.sanger.ac.uk/Homo_sapiens/Location/Overview/region?db=core;g=OTTHUMG 00000021557;r=X:52057788–52857787. Accessed on July 23, 2011.
- 14 Wang T, Fan L, Watanabe Y, McNeill P, Fanger GR, Persing DH, Reed SG. L552S, an alternatively spliced isoform of XAGE-1, is over-expressed in lung adenocarcinoma. Oncogene 2001; 20: 7699–709.
- 15 Egland KA, Kumar V, Duray P, Pastan I. Characterization of overlapping XAGE-1 transcripts encoding a cancer testis antigen expressed in lung, breast, and other types of cancers. Mol Cancer Ther 2002; 1: 441–50.
- 16 Zendman AJ, van Kraats AA, den Hollander AI, Weidle UH, Ruiter DJ, van Muijen GN. Characterization of XAGE-1b, a short major transcript of cancer/testis-associated gene XAGE-1, induced in melanoma metastasis. Int J Cancer 2002; 97: 195–204.
- 17 Zendman AJ, Van Kraats AA, Weidle UH, Ruiter DJ, Van Muijen GN. The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's sarcoma. Int J Cancer 2002; 99: 361–69.
- 18 Ali Eldib AM, Ono T, Shimono M, Kaneko M, Nakagawa K, Tanaka R, Noguchi Y, Nakayama E. Immunoscreening of a cDNA library from a lung cancer cell line using autologous patient serum: Identification of XAGE-1b as a dominant antigen and its immunogenicity in lung adenocarcinoma. Int J Cancer 2004; 108: 558–63.
- 19 Sato S, Noguchi Y, Ohara N, Uenaka A, Shimono M, Nakagawa K, Koizumi F, Ishida T, Yoshino T, Shiratori Y, Nakayama E. Identification of XAGE-1 isoforms: predominant expression of XAGE-1b in testis and tumors. Cancer Immun 2007; 7: 5.
- 20 Kikuchi E, Yamazaki K, Nakayama E, Sato S, Uenaka A, Yamada N, Oizumi S, Dosaka-Akita H, Nishimura M. Prolonged survival of patients with lung adenocarcinoma expressing XAGE-1b and HLA class I antigens. Cancer Immun 2008; 8: 13.
- 21 Eikawa S, Ohue Y, Kitaoka K, Aji T, Uenaka A, Oka M, Nakayama E. Enrichment of Foxp3(+) CD4 regulatory T cells in migrated T cells to IL-6- and IL-8-expressing tumors through predominant induction of CXCR1 by IL-6. J Immunol 2010; 185: 6734–40.
- 22 Nakagawa K, Noguchi Y, Uenaka A, Sato S, Okumura H, Tanaka M, Shimono M, Ali Eldib AM, Ono T, Ohara N, Yoshino T, Yamashita K, Tsunoda T, Aoe M, Shimizu N, Nakayama E. XAGE-1 expression in non-small cell lung cancer and antibody response in patients. Clin Cancer Res 2005; 11: 5496–503.
- 23 Stockert E, Jäger E, Chen YT, Scanlan MJ, Gout I, Karbach J, Arand M, Knuth A, Old LJ. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med 1998; 187: 1349–54.
- 24 Chen YT, Scanlan MJ, Sahin U, Türeci O, Gure AO, Tsang S, Williamson B, Stockert E, Pfreundschuh M, Old LJ. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci U S A 1997; 94: 1914–18.
- 25 Van den Eynde BJ, van der Bruggen P. T cell defined tumor antigens. Curr Opin Immunol 1997; 9: 684–93.
- 26
Türeci O,
Chen YT,
Sahin U,
Güre AO,
Zwick C,
Villena C,
Tsang S,
Seitz G,
Old LJ,
Pfreundschuh M.
Expression of SSX genes in human tumors.
Int J Cancer
1998;
77:
19–23.
10.1002/(SICI)1097-0215(19980703)77:1<19::AID-IJC4>3.0.CO;2-2 CAS PubMed Web of Science® Google Scholar
- 27 Reuschenbach M, von Knebel Doeberitz M, Wentzensen N. A systematic review of humoral immune responses against tumor antigens. Cancer Immunol Immunother 2009; 58: 1535–44.
- 28 Gnjatic S, Atanackovic D, Jäger E, Matsuo M, Selvakumar A, Altorki NK, Maki RG, Dupont B, Ritter G, Chen YT, Knuth A, Old LJ. Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl Acad Sci U S A 2003; 100: 8862–67.
- 29 Jäger E, Nagata Y, Gnjatic S, Wada H, Stockert E, Karbach J, Dunbar PR, Lee SY, Jungbluth A, Jäger D, Arand M, Ritter G, et al. Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci U S A 2000; 97: 4760–65.
- 30 Gnjatic S, Nishikawa H, Jungbluth AA, Güre AO, Ritter G, Jäger E, Knuth A, Chen YT, Old LJ. NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res 2006; 95: 1–30.
- 31 Valmori D, Dutoit V, Liénard D, Rimoldi D, Pittet MJ, Champagne P, Ellefsen K, Sahin U, Speiser D, Lejeune F, Cerottini JC, Romero P. Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients. Cancer Res 2000; 60: 4499–506.
- 32 Morishita Y, Uenaka A, Kaya S, Sato S, Aji T, Nakayama E. HLA-DRB1*0410-restricted recognition of XAGE-1b37–48 peptide by CD4 T cells. Microbiol Immunol 2007; 51: 755–62.
- 33 Shimono M, Uenaka A, Noguchi Y, Sato S, Okumura H, Nakagawa K, Kiura K, Tanimoto M, Nakayama E. Identification of DR9-restricted XAGE antigen on lung adenocarcinoma recognized by autologous CD4 T-cells. Int J Oncol 2007; 30: 835–40.
Citing Literature
