Avoiding tolerance against prostatic antigens with subdominant peptide epitopes

A potential novel therapy for prostate cancer is the induction of immune responses to normal prostate-associated antigens (PAA). One approach is to use synthetic peptides from PAA to educate T cells as a means of developing a defined and specific immunotherapy for prostate cancer. A likely major hurdle when using normal PAA for this type of therapy is the tolerance that the immune system may already have for PAA. To evaluate mechanisms for overcoming tolerance, the authors assessed the level of tolerance to SV40T antigen in a transgenic mouse. The SV40T antigen is selectively expressed in the prostates of mice from the transgenic adenocarcinoma mouse prostate (TRAMP) model. The authors have shown that TRAMP mice are tolerant to a dominant cytotoxic T-lymphocyte (CTL) epitope from the SV40T antigen compared with nontransgenic littermates. The tolerance was exhibited as early as 4 weeks and as late as 24 weeks. The use of multiple injections of an oligonucleotide that contains an unmethylated CpG induced high levels of hematopoiesis but did not overcome the tolerance. Injection of an antibody to activate CD40 increased the CTL response in normal mice but also did not overcome tolerance. However, tolerance in the TRAMP mice was avoided when an epitope that had previously been characterized as a subdominant epitope was administered. The authors are investigating the potential of subdominant epitopes to induce prostatitis and antitumor responses. The results of this work should facilitate the development of immune-based therapies for prostate cancer.