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'-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.
Highlights
Prostate cancer is the most frequently diagnosed and second leading cause of cancer-related death among American men, and a significant health concern worldwide [1]
A comprehensive study evaluating synovial sarcoma X chromosome breakpoint (SSX) family member mRNA and protein expression had not been conducted for prostate cancer cell lines or tumor tissues
We found that SSX2 mRNA transcripts were commonly expressed in prostate cancer cell lines at baseline, whereas SSX1 and SSX5 were frequently inducible with epigenetic modifying agents (EMA)
Summary
Prostate cancer is the most frequently diagnosed and second leading cause of cancer-related death among American men, and a significant health concern worldwide [1]. Organ-confined prostate cancer is initially treated by surgery or radiation therapy; approximately one-third of patients relapse, and another one-third of these patients will develop life-threatening, castrate-resistant tumors [1,2,3]. Sipuleucel-T was recently U.S Food and Drug Administration approved as the first immunotherapeutic vaccine shown to improve overall survival in patients with castrateresistant prostate cancer [4]. The success of this approach suggests that other simpler immunotherapies could be investigated targeting additional antigens, potentially with the goal of preventing the development of castrate-resistant metastatic disease.
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