CTAG1B explained

Cancer/testis antigen 1 also known as LAGE2 or LAGE2B is a protein that in humans is encoded by the CTAG1B gene.^{[1] [2] [3]} It is most often referenced by its alias NY-ESO-1.

Cancer/Testis Antigen 1B is a protein belonging to the family of Cancer Testis Antigens (CTA) that are expressed in a variety of malignant tumours at the mRNA and protein levels, but also restricted to testicular germ cells in normal adult tissues. A clone of CTAG gene was originally identified by immunological methods in oesophageal carcinoma using patient serum.^[4] The aberrant re-expression of CTAs is induced by molecular mechanisms including DNA demethylation, histone post-translational modification, and microRNA-mediated regulation. The effect of DNA demethylation is evident by the capability of demethylating agents, such as 5-aza-2-deoxycytidine, to induce CTAs re-expression in tumour cells but not in normal epithelial cells.

Gene

CTAG1B is located on the long arm of chromosome X (Xq28), containing three exons that are approximately 8 Kb in length. CTAG1B is found to have a neighbouring gene of identical sequence: CTAG1A.

Protein

The gene encodes a 180-amino acid polypeptide, expressed from 18 weeks during embryonic development until birth in human fetal testis. It is also strongly expressed in spermatogonia and in primary spermatocytes of adult testis, but not in post-meiotic cells or testicular somatic cells.^[5] Structurally, CTAG1B features a glycine-rich N-terminal region, as well as a hydrophobic C-terminal region with a Pcc-1 domain. The protein has been shown to be homologous to two other CTAs located in the same region: LAGE-1 and ESO3.^[6] The exact function of CTAG1B remains to be unknown. Studies have suggested its role in cell cycle progression and growth, although not being elusive, through the analysis of CTAG1B's structure and expression pattern. The coexpression of CTAG1B with melanoma antigen gene C1 (MAGE-C1), another CTA, further supports its involvement in cell cycle regulation and apoptosis, due to the role of MAGE proteins in these processes. Moreover, its restricted expression pattern in male germ cells suggests its role in germ cell self-renewal or differentiation, supported by the nuclear localization of CTAG1B in mesenchymal stem cells in contrast to its cytoplasmic expression in cancer cells.^[7]

Humoral Immune Response

It is also believed that cancer-testis antigens are immunogenic proteins, since many members of the family have been shown to induce spontaneous cellular and humoral immune responses in patients with advanced stage tumours. The first reported simultaneous humoral and cellular response against CTAG1B was from a metastatic melanoma patient. 3 HLA-A2 restricted epitopes in CTAG1B were identified as the recognition sites for CD8+ cytotoxic T lymphocytes.^[8] Integrated humoral immune responses against CTAG1B have been detected in patients with: Multiple myeloma,^[9] breast cancer,^[10] non small-cell lung carcinoma,^[11] and ovarian cancer.^[12] As such, CTAG1B is believed to be a promising candidate for cancer immunotherapy due to its exclusive expression in normal tissues and re expression in tumour cells, as well as its high immunogenicity. These features also suggest a limited off-target toxicity of CTAG1B-based cancer therapies. The immunisation with CTAG1B could be a successful approach to induce antigen specific immune responses in cancer patients. Up until May 2018, there have been 12 clinical trials registered using a CTAG1B cancer vaccine, 23 using modified T cells, and 13 using combinatorial immunotherapy.

Examining the expression of a number of CTA genes in 23 samples of sporadic medullary thyroid carcinoma has revealed that CTAG1B expression significantly correlates with tumour recurrence. A humoral response against this CTA was detected in 54.5% of CTAG1B-expressing patients, and in 1 of 6 patients with an CTAG1B-negative tumour. Anti-CTAG1B antibodies were present in 35.7%, demonstrating that medullary thyroid carcinoma is associated with humoral immune response to CTAG1B.^[13] Another study has shown that CTAG1B binding to CALR on macrophages and dendritic cells provides a link between CTAG1B, the innate immune system, and possibly the adaptive immune response against CTAG1B.^[14]

Further reading

• Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT . Cancer/testis antigens: an expanding family of targets for cancer immunotherapy . Immunological Reviews . 188 . 22–32 . October 2002 . 12445278 . 10.1034/j.1600-065X.2002.18803.x . 24718232 .
• 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 . Proceedings of the National Academy of Sciences of the United States of America . 94 . 5 . 1914–8 . March 1997 . 9050879 . 20017 . 10.1073/pnas.94.5.1914 . 1997PNAS...94.1914C . free .
• Lethé B, Lucas S, Michaux L, De Smet C, Godelaine D, Serrano A, De Plaen E, Boon T . LAGE-1, a new gene with tumor specificity . International Journal of Cancer . 76 . 6 . 903–8 . June 1998 . 9626360 . 10.1002/(SICI)1097-0215(19980610)76:6<903::AID-IJC22>3.0.CO;2-1 . free .
• Wang RF, Johnston SL, Zeng G, Topalian SL, Schwartzentruber DJ, Rosenberg SA . A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames . Journal of Immunology . 161 . 7 . 3598–606 . October 1998 . 10.4049/jimmunol.161.7.3596 . 9759882 . 21146485 .
• De Smet C, Lurquin C, Lethé B, Martelange V, Boon T . DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter . Molecular and Cellular Biology . 19 . 11 . 7327–35 . November 1999 . 10523621 . 84726 . 10.1128/MCB.19.11.7327 .
• Schultz-Thater E, Noppen C, Gudat F, Dürmüller U, Zajac P, Kocher T, Heberer M, Spagnoli GC . NY-ESO-1 tumour associated antigen is a cytoplasmic protein detectable by specific monoclonal antibodies in cell lines and clinical specimens . British Journal of Cancer . 83 . 2 . 204–8 . July 2000 . 10901371 . 2363487 . 10.1054/bjoc.2000.1251 .
• Rimoldi D, Rubio-Godoy V, Dutoit V, Lienard D, Salvi S, Guillaume P, Speiser D, Stockert E, Spagnoli G, Servis C, Cerottini JC, Lejeune F, Romero P, Valmori D . Efficient simultaneous presentation of NY-ESO-1/LAGE-1 primary and nonprimary open reading frame-derived CTL epitopes in melanoma . Journal of Immunology . 165 . 12 . 7253–61 . December 2000 . 11120859 . 10.4049/jimmunol.165.12.7253 . free .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Jungbluth AA, Chen YT, Stockert E, Busam KJ, Kolb D, Iversen K, Coplan K, Williamson B, Altorki N, Old LJ . Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues . International Journal of Cancer . 92 . 6 . 856–60 . June 2001 . 11351307 . 10.1002/ijc.1282 . free .
• Goydos JS, Patel M, Shih W . NY-ESO-1 and CTp11 expression may correlate with stage of progression in melanoma . The Journal of Surgical Research . 98 . 2 . 76–80 . June 2001 . 11397121 . 10.1006/jsre.2001.6148 .
• Zarour HM, Maillere B, Brusic V, Coval K, Williams E, Pouvelle-Moratille S, Castelli F, Land S, Bennouna J, Logan T, Kirkwood JM . NY-ESO-1 119-143 is a promiscuous major histocompatibility complex class II T-helper epitope recognized by Th1- and Th2-type tumor-reactive CD4+ T cells . Cancer Research . 62 . 1 . 213–8 . January 2002 . 11782380 .
• Satie AP, Rajpert-De Meyts E, Spagnoli GC, Henno S, Olivo L, Jacobsen GK, Rioux-Leclercq N, Jégou B, Samson M . The cancer-testis gene, NY-ESO-1, is expressed in normal fetal and adult testes and in spermatocytic seminomas and testicular carcinoma in situ . Laboratory Investigation; A Journal of Technical Methods and Pathology . 82 . 6 . 775–80 . June 2002 . 12065688 . 10.1097/01.lab.0000017169.26718.5f . free .
• Nagata Y, Ono S, Matsuo M, Gnjatic S, Valmori D, Ritter G, Garrett W, Old LJ, Mellman I . Differential presentation of a soluble exogenous tumor antigen, NY-ESO-1, by distinct human dendritic cell populations . Proceedings of the National Academy of Sciences of the United States of America . 99 . 16 . 10629–34 . August 2002 . 12138174 . 124995 . 10.1073/pnas.112331099 . 2002PNAS...9910629N . free .
• Resnick MB, Sabo E, Kondratev S, Kerner H, Spagnoli GC, Yakirevich E . Cancer-testis antigen expression in uterine malignancies with an emphasis on carcinosarcomas and papillary serous carcinomas . International Journal of Cancer . 101 . 2 . 190–5 . September 2002 . 12209997 . 10.1002/ijc.10585 . free .
• Peng LP, Liu HY, Ran YL, Sun LX, Yu L, Yang ZH . [Expression of NY-ESO-1 gene in human esophageal carcinoma and its cloning] . AI Zheng = Aizheng = Chinese Journal of Cancer . 21 . 5 . 469–72 . May 2002 . 12452034 .
• 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 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 15 . 8862–7 . July 2003 . 12853579 . 166404 . 10.1073/pnas.1133324100 . 2003PNAS..100.8862G . free .

Notes and References

1. Chen YT, Boyer AD, Viars CS, Tsang S, Old LJ, Arden KC . Genomic cloning and localization of CTAG, a gene encoding an autoimmunogenic cancer-testis antigen NY-ESO-1, to human chromosome Xq28 . Cytogenetics and Cell Genetics . 79 . 3–4 . 237–40 . Jun 1998 . 9605863 . 10.1159/000134734 .
2. Aradhya S, Bardaro T, Galgóczy P, Yamagata T, Esposito T, Patlan H, Ciccodicola A, Munnich A, Kenwrick S, Platzer M, D'Urso M, Nelson DL . Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes . Human Molecular Genetics . 10 . 22 . 2557–67 . October 2001 . 11709543 . 10.1093/hmg/10.22.2557 . free .
3. Web site: Entrez Gene: CTAG1B cancer/testis antigen 1B.
4. 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 . Proceedings of the National Academy of Sciences of the United States of America . 94 . 5 . 1914–8 . March 1997 . 9050879 . 20017 . 10.1073/pnas.94.5.1914 . 1997PNAS...94.1914C . free .
5. Satie AP, Rajpert-De Meyts E, Spagnoli GC, Henno S, Olivo L, Jacobsen GK, Rioux-Leclercq N, Jégou B, Samson M . The cancer-testis gene, NY-ESO-1, is expressed in normal fetal and adult testes and in spermatocytic tumors and testicular carcinoma in situ . Laboratory Investigation; A Journal of Technical Methods and Pathology . 82 . 6 . 775–80 . June 2002 . 12065688 . 10.1097/01.LAB.0000017169.26718.5F . free .
6. Thomas R, Al-Khadairi G, Roelands J, Hendrickx W, Dermime S, Bedognetti D, Decock J . NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives . Frontiers in Immunology . 9 . 947 . 2018 . 29770138 . 5941317 . 10.3389/fimmu.2018.00947 . free .
7. Cho HJ, Caballero OL, Gnjatic S, Andrade VC, Colleoni GW, Vettore AL, Outtz HH, Fortunato S, Altorki N, Ferrera CA, Chua R, Jungbluth AA, Chen YT, Old LJ, Simpson AJ . Physical interaction of two cancer-testis antigens, MAGE-C1 (CT7) and NY-ESO-1 (CT6) . Cancer Immunity . 6 . 12 . December 2006 . 17137291 .
8. 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 . The Journal of Experimental Medicine . 187 . 2 . 265–70 . January 1998 . 9432985 . 2212106 . 10.1084/jem.187.2.265 .
9. Toor AA, Payne KK, Chung HM, Sabo RT, Hazlett AF, Kmieciak M, Sanford K, Williams DC, Clark WB, Roberts CH, McCarty JM, Manjili MH . Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen-specific cellular immunity . British Journal of Haematology . 158 . 6 . 700–11 . September 2012 . 22816680 . 4968567 . 10.1111/j.1365-2141.2012.09225.x .
10. Ademuyiwa FO, Bshara W, Attwood K, Morrison C, Edge SB, Karpf AR, James SA, Ambrosone CB, O'Connor TL, Levine EG, Miliotto A, Ritter E, Ritter G, Gnjatic S, Odunsi K . NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer . PLOS ONE . 7 . 6 . e38783 . 2012 . 22761704 . 3386262 . 10.1371/journal.pone.0038783 . 2012PLoSO...738783A . free .
11. Nakamura Y, Noguchi Y, Satoh E, Uenaka A, Sato S, Kitazaki T, Kanda T, Soda H, Nakayama E, Kohno S . Spontaneous remission of a non-small cell lung cancer possibly caused by anti-NY-ESO-1 immunity . Lung Cancer . 65 . 1 . 119–22 . July 2009 . 19193472 . 10.1016/j.lungcan.2008.12.020 . 10069/23183 . free .
12. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, Old LJ, Odunsi K . Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer . Proceedings of the National Academy of Sciences of the United States of America . 107 . 17 . 7875–80 . April 2010 . 20385810 . 2867907 . 10.1073/pnas.1003345107 . 2010PNAS..107.7875M . free .
13. Maio M, Coral S, Sigalotti L, Elisei R, Romei C, Rossi G, Cortini E, Colizzi F, Fenzi G, Altomonte M, Pinchera A, Vitale M . Analysis of cancer/testis antigens in sporadic medullary thyroid carcinoma: expression and humoral response to NY-ESO-1 . The Journal of Clinical Endocrinology and Metabolism . 88 . 2 . 748–54 . February 2003 . 12574209 . 10.1210/jc.2002-020830 . free .
14. Zeng G, Aldridge ME, Tian X, Seiler D, Zhang X, Jin Y, Rao J, Li W, Chen D, Langford MP, Duggan C, Belldegrun AS, Dubinett SM . Dendritic cell surface calreticulin is a receptor for NY-ESO-1: direct interactions between tumor-associated antigen and the innate immune system . Journal of Immunology . 177 . 6 . 3582–9 . September 2006 . 16951317 . 10.4049/jimmunol.177.6.3582 . free .