Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatogonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.
The Ludwig Institute for Cancer Research (LICR) maintains the "CTDatabase." This database is an authoritative list of known CT antigens. It also serves as a repository into which new candidates can be entered.
Important CT antigens in cancer therapy include MAGE-A1, MAGE-A3, MAGE-A4, NY-ESO-1, PRAME, CT83 and SSX2.
History
With the development of tumor-associated antigens (TAA), the first clone of a human tumor antigen, melanoma antigen-1 (MAGE-1) was reported in 1990s, which elicited an autologous cytotoxic T-lymphocyte (CTL) response in a melanoma patient. Further studies found that MAGE-1 (renamed MAGE-A1 later) was expressed in various cancers of different histological origin but not in normal tissues excluding testis and placenta. Later on, using T-cell epitope cloning technology, other tumor antigens with same properties were identified, including MAGE-A2, MAGE-A3, BAGE and GAGE-1. With the new approach, serological analysis of cDNA expression libraries (SEREX), several novel similar antigens were discovered, including SSX-2, NY-ESO-1, etc. Beyond these immunological methods, some gene expression techniques, including mRNA pools comparison, differential display, cDNA oligonucleotide array analysis and bioinformatic analysis, identified a multitude of tumor genes with a cancer/testis restricted expression profile. As the growing of this family, this type of tumor antigens, the genes of which expressing limitedly in malignancies of various histotypes, but not in normal tissue except testis and placenta, was named cancer testis antigen (CT antigens) by Old (1997) and Chen (1998). So far, at least 70 families of CT antigens with over 140 members have been identified and listed in a database established by the Ludwing Institute for Cancer Research.
Category
CT antigens can be divided by whether they are encoded on the X chromosome (X-CT antigens genes) or not (non-X-CT antigens genes). It has been estimated that 10% of genes on the X chromosome belong to X-CT antigens families. The X-CT antigens genes represent more than half of all CT antigens and often constitute multigene families organized in well-defined clusters long the X chromosome, while the genes of non-X-CT antigens are distributed throughout the genome and are mostly single-copy genes.
In normal testis, X-CT antigens genes are expressed primarily on the spermatogonia that are proliferate germ cells, while non-X-CT antigens are expressed in later stages of germ-cell differentiation, such as on spermatocytes. In normal placenta, CT antigens genes are less common, and MAGE-A3, MAGE-8, MAGE-A10, XAGE-2 and XAGE-3 have been found there. The mRNA of CT antigens was also found in some somatic tissues such as pancreas, liver and spleen, but the level is normally less than 1% of that in testis.
The expression of CT antigens genes were measured mainly by RT-PCR in transcription level and by immunohistochemistry (IHC) analysis in protein level. In tumor tissues, CT antigens are distributed widely but heterogeneously, expressing largely in melanoma, bladder and non-small cell lung cancers, moderately in breast and prostate cancers, poorly in kidney and colon cancers and in hematologic malignancies. Some reports suggest that multiple CT antigens tend to be co-expressed in the same neoplastic lesion.