Avoiding tolerance against prostatic antigens with subdominant peptide epitopes

A potential novel therapy for prostate cancer is the induction of immune re sponses to normal prostate-associated antigens (PAA). One approach is to us e synthetic peptides from PAA to educate T cells as a means of developing a defined and specific immunotherapy for prostate cancer. A likely major hur dle when using normal PAA for this type of therapy is the tolerance that th e immune system may already have for PAA. To evaluate mechanisms for overco ming tolerance, the authors assessed the level of tolerance to SV40T antige n 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 c ytotoxic T-lymphocyte (CTL) epitope from the SV40T antigen compared with no ntransgenic littermates. The tolerance was exhibited as early as 4 weeks an d 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 toleran ce. However, tolerance in the TRAMP mice was avoided when an epitope that h ad previously been characterized as a subdominant epitope was administered. The authors are investigating the potential of subdominant epitopes to ind uce prostatitis and antitumor responses. The results of this work should fa cilitate the development of immune-based therapies for prostate cancer.