Six-transmembrane epithelial antigen of the postate (STREAP): a potential target of immunotherapy of prostate cancer.

Immunotherapy has been proposed as a complementary or alternative therapy for the treatment of advanced prostate cancer (PC), one of the leading causes of tumor-related mortality in men. From different approaches that have been tested in recent years, it is now becoming more evident that the choice of the appropriate antigen to target is crucial for the best outcome. Generally tumor-associated antigens (TAAs) undergo peripheral tolerance during tumor progression, which dampens the efficacy of vaccination protocols. It can be hypothesized that the kinetic and depth of immune tolerance varies depending on the timing and relative expression of the TAA. These differences may represent a key for successful immunotherapy approaches even in patients with advanced disease. Aim of my thesis was to investigate the dynamics of CD8+ T cells specific for normal tissue antigens over-expressed during the spontaneous tumor development and progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, a primary model of human PC. We have found that Prostate Stem Cell Antigen (PSCA) and Six-Transmembrane Epithelial Antigen of the Prostate (STEAP), two well known PC-associated antigens, behave differently in term of immunological response when compared with the transgenic Tag IV antigen, which drives oncogenesis in TRAMP mice. While a dendritic cells (DC)-based immunization was able to elicit measurable immune responses for all three antigens in young males affected by mouse prostate intraepithelial neoplasia (mPIN), aged mice affected by PC progressively lost immunity against Tag IV and in part for PSCA, but not against STEAP. The findings correlated with the amount of antigens expressed in the prostate, therefore suggesting that tolerance against this type of TAA follows the same rule of that induced for tissue-associated antigens in peripheral tissues: the more the antigen is expressed the more tolerance is profound. Finally, a combined therapy of allotransplantation and DC-STEAP vaccination effectively reduced tumor burden in TRAMP mice, underlying how this therapeutic strategy when targeted to a reliable antigen is able to restore cancer immunosurveillance.