Biology:CTAG1B

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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),[4] 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.[6]

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]

References

  1. ↑ "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. doi:10.1159/000134734. PMID 9605863. 
  2. ↑ "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. doi:10.1093/hmg/10.22.2557. PMID 11709543. 
  3. ↑ "Entrez Gene: CTAG1B cancer/testis antigen 1B". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1485. 
  4. ↑ 4.0 4.1 "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. doi:10.1073/pnas.94.5.1914. PMID 9050879. Bibcode: 1997PNAS...94.1914C. 
  5. ↑ "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. doi:10.1097/01.LAB.0000017169.26718.5F. PMID 12065688. 
  6. ↑ 6.0 6.1 "NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives". Frontiers in Immunology 9: 947. 2018. doi:10.3389/fimmu.2018.00947. PMID 29770138. 
  7. ↑ "Physical interaction of two cancer-testis antigens, MAGE-C1 (CT7) and NY-ESO-1 (CT6)". Cancer Immunity 6: 12. December 2006. PMID 17137291. 
  8. ↑ "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. doi:10.1084/jem.187.2.265. PMID 9432985. 
  9. ↑ "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. doi:10.1111/j.1365-2141.2012.09225.x. PMID 22816680. 
  10. ↑ "NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer". PLOS ONE 7 (6): e38783. 2012. doi:10.1371/journal.pone.0038783. PMID 22761704. Bibcode: 2012PLoSO...738783A. 
  11. ↑ "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. doi:10.1016/j.lungcan.2008.12.020. PMID 19193472. 
  12. ↑ "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. doi:10.1073/pnas.1003345107. PMID 20385810. Bibcode: 2010PNAS..107.7875M. 
  13. ↑ "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. doi:10.1210/jc.2002-020830. PMID 12574209. 
  14. ↑ "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. doi:10.4049/jimmunol.177.6.3582. PMID 16951317. 

Further reading

External links



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