The SSX family of cancer-testis antigens as target proteins for tumor therapy

Abstract

Cancer-testis antigens (CTAs) represent an expanding class of tumor-associated proteins defined on the basis of their tissue-restricted expression to testis or ovary germline cells and frequent ectopic expression in tumor tissue. The expression of CTA in MHC class I-deficient germline cells makes these proteins particularly attractive as immunotherapeutic targets because they serve as essentially tumor-specific antigens for MHC class I-restricted CD8+ T cells. Moreover, because CTAs are expressed in many types of cancer, any therapeutic developed to target these antigens might have efficacy for multiple cancer types. Of particular interest among CTAs is the synovial sarcoma X chromosome breakpoint (SSX) family of proteins, which includes ten highly homologous family members. Expression of SSX proteins in tumor tissues has been associated with advanced stages of disease and worse patient prognosis. Additionally, both humoral and cell-mediated immune responses to SSX proteins have been demonstrated in patients with tumors of varying histological origin, which indicates that natural immune responses can be spontaneously generated to these antigens in cancer patients. The current review will describe the history and identification of this family of proteins, as well as what is known of their function, expression in normal and malignant tissues, and immunogenicity.

Figure 1

Protein homology and conserved domains among SSX orthologues. Shown is a sequence alignment of species-specific SSX protein sequences from canine, horse, human, macaque, chimpanzee, marmoset, mouse, and rat sources. Blue highlighting represents >75% sequence identity with consensus sequence shown on the bottom. The KRAB and SSXRD domain regions denoted by solid green bars are shown below the sequence alignment.

Figure 2

Functional interactions of the SSX proteins. The RAB3IP and SSX2IP protein interaction with the SSX KRAB domain and LHX4 and PcG protein interactions with the SSXRD domain are depicted. Dynamic intracellular and intranuclear interactions are highlighted.