Expression and Immunotherapeutic Targeting of the SSX Family of Cancer–Testis Antigens in Prostate Cancer

Abstract

Recent U.S. Food and Drug Administration approval of the first immunotherapy for prostate cancer encourages efforts to improve immune targeting of this disease. The synovial sarcoma X chromosome breakpoint (SSX) proteins comprise a set of cancer-testis antigens that are upregulated in MHC class I-deficient germline cells and in various types of advanced cancers with a poor prognosis. Humoral and cell-mediated immune responses to the SSX family member SSX2 can arise spontaneously in prostate cancer patients. Thus, SSX2 and other proteins of the SSX family may offer useful targets for tumor immunotherapy. In this study, we evaluated the expression of SSX family members in prostate cancer cell lines and tumor biopsies to identify which members might be most appropriate for immune targeting. We found that SSX2 was expressed most frequently in prostate cell lines, but that SSX1 and SSX5 were also expressed after treatment with the DNA demethylating agent 5-aza-2 0 -deoxycytidine. Immunohistochemical analysis of microarrayed tissue biopsies confirmed a differential level of SSX protein expression in human prostate cancers. Notably, SSX expression in patient tumor samples was restricted to metastatic lesions (5/22; 23%) and no expression was detected in primary prostate tumors examined (0/73; P < 0.001). We determined that cross-reactive immune responses to a dominant HLA-A2-specific SSX epitope (p103-111) could be elicited by immunization of A2/DR1 transgenic mice with SSX vaccines. Our findings suggest that multiple SSX family members are expressed in metastatic prostate cancers which are amenable to simultaneous targeting. Cancer Res; 71(21); 6785-95. Ó2011 AACR.

Mini-intronic plasmid vaccination elicits tolerant LAG3+CD8+T cells and inferior antitumor responses

“…This was evaluated in a system we have previously reported using a plasmid DNA vaccine encoding the tumor associated cancer-testis antigen SSX2 (Synovial Sarcoma, X Breakpoint 2), 27 relevant HLA-A2 transgenic mice that permit analysis of epitope specific immunity, and a syngeneic tumor cell line model engineered to express the antigen of interest. [28][29][30] We found that MIP-SSX2 immunization elicited greater frequencies of tetramer positive CD8 T cells and antigen-specific IFNg responses, as others have previously reported with minicircles. However, we observed that while MIP-SSX2 protected against tumor challenge in a prophylactic setting, there was a paradoxical loss of antitumor effect following treatment of established tumors.…”

“…We first constructed a DNA minicircle (DMC-SSX2) by cloning the expression cassette of pTVG-SSX2 (a plasmid encoding the cancer-testis antigen SSX2 that we have previously described) 30,31 into a minicircle production vector (Figs. 1A and B).…”

Synaptonemal complex protein 3 is a prognostic marker in cervical cancer

“…CTAs are restricted in normal tissues to germ cells of the testis, with occasional expression in female reproductive organs, and are expressed in histologically different types of malignant human tumors [1][2][3][4]. The tumor restricted expression pattern of CTAs makes them an interesting target for immunotherapeutic approaches [3,5]. The role of CTA expression in tumor cells remains unclear, and thus is an area of active research.…”

Cancer/testis antigens: novel tools for discerning aggressive and non-aggressive prostate cancer

“…35 Lethe et al 36 reported that expression of MAGE-A1 was observed in 10.8% of carcinoma samples, whereas multi-MAGE-A and NY-ESO-1/LAGE-1 stained 85.9% and 84.8% of samples using immunohistochemistry, suggesting that a panel of CTAs rather than individual ones maybe more valuable as biomarkers. Recently, Smith et al 37 showed that SSX protein expression was restricted mainly to metastatic prostate cancer and not expressed in any primary prostate cancer using immunohistochemistry.…”