The biology of cancer testis antigens: putative function, regulation and therapeutic potential

Abstract

Cancer testis antigens (CTA) are a large family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues except for testis and placenta. This tumor-restricted pattern of expression, together with their strong in vivo immunogenicity, identified CTA as ideal targets for tumor-specific immunotherapeutic approaches, and prompted the development of several clinical trials of CTA-based vaccine therapy. Driven by this practical clinical interest, a more detailed characterization of CTA biology has been recently undertaken. So far, at least 70 families of CTA, globally accounting for about 140 members, have been identified. Most of these CTA are expressed during spermatogenesis, but their function is still largely unknown. Epigenetic events, particularly DNA methylation, appear to be the primary mechanism regulating CTA expression in both normal and transformed cells, as well as in cancer stem cells. In view of the growing interest in CTA biology, the aim of this review is to provide the most recent information on their expression, regulation and function, together with a brief summary of the major clinical trials involving CTA as therapeutic agents. The pharmacologic modulation of CTA expression profiles on neoplastic cells by DNA hypomethylating drugs will also be discussed as a feasible approach to design new combination therapies potentially able to improve the clinical efficacy of currently adopted CTA-based immunotherapeutic regimens in cancer patients.

Figure 1

Epigenetic regulation of CTA expression. Transcriptionally inactive CTA genes (upper panel) are characterized by the presence of methylated cytosines within the promoter region (orange circles), which is carried out and sustained by DNA methyltransferases (DNMT). Inhibition of CTA genes transcription may directly derive from methylated recognition sequence preventing the binding of transcription factors (TF), or may be a consequence of the binding of methyl‐CpG‐binding proteins (MBP), which prevent CTA gene expression by recruiting chromatin remodeling co‐repressor complexes (CR). The presence within these CR of histone deacetylases (HDAC) that mediate deacetylation of histones (blue N‐terminal tails), and of histone methyltransferases (HMT) that catalyze the methylation of histones (red N‐terminal tails), causes the condensation of chromatin and makes it inaccessible to TF, thus playing an important accessory role to DNA methylation in repressing CTA expression (red arrow). On the other hand, demethylated CTA promoters (green circles) prevent the binding of MBP and CR, and are occupied by complexes including TF and histone acetyltransferases (HAT) that mediate acetylation of histones (pink N‐terminal tails), finally resulting in a transcriptionally active CTA genes (green arrow).