The hypothesis of the proposed studies is that tumor-associated antigen (TAA) tolerance can be attenuated, by modulating peripheral TAA expression, thereby enabling recombinant, TAA-encoding vaccines to elicit effective anti-tumor, TAA-specific immune responses. The proposal seeks to determine avenues by which host mechanisms promoting prostate cancer TAA-specific tolerance can be circumvented; the proposed project is intended as an expanded and refined replacement of the PI's ongoing R-29 project (which shares similar goals). Preliminary studies assessed the utility of TRAMP mice (which develop prostate cancer due to prostate-specific SV40 T antigen, Tag) for this purpose. First, a novel vaccinia vector encoding the non-oncogenic domains of Tag (vac-mTag) was constructed, and vac-mTag induced immunity against Tag as a non-self antigen in vitro and in vivo. Second, surrogate longitudinal endpoints for measuring TRAMP prostate cancer response to intervention (therapy), including sequential magnetic resonance imaging (MRI) were established and validated, with castration used as a test intervention. Third, TRAMP mouse immunization with the Tag-encoding vaccinia was shown to break cytotoxic T cell (CTL) tolerance to the androgen-responsive autologous, Tag oncogene in juvenile TRAMP mice lacking abundant Tag expression, but not in component of Tag-specific CTL do not undergo clonal elimination in low-Tag expressing juvenile mice prior to onset of prostate tumorigenesis, and Tag-specific tolerance in these mice can be broken via vac-m Tag immunization. Based on these preliminary findings, the proposal will address the following aims: 1) To evaluate effects of peripheral (prostatic) expression levels of antigen and tumorigenesis toward potentiation and maintenance of prostatic TAA tolerance; 2) To evaluate methods of TAA immunization to break TAA-specific tolerance; and 3) To determine whether Tag-specific T cells undergo peripheral apoptotic elimination, anergy, or reversible inactivation and evaluate possible CTLA-4 function in this process. The outcome of these studies will help guide the development of effective immunization strategies targeting hormone-responsive TAA in human prostate and other cancers.
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