Androgen Ablation Combined With CTLA-4 Blockade-Based Immunotherapy as a Treatment for Prostate Cancer

摘要

Manipulations capable of repealing host tolerance to induce T cell- mediated prostate tissue-specific responses are of central importance to immunotherapeutic approaches to prostate cancer treatment. Hence in the current proposal, we test whether androgen ablation (by castration) can induce T cell responses targeting murine prostate epithelial and tumor cells. We previously showed that castration of TRAMP mice results in prostate and tumor infiltration by antigen presenting cells (APC's) as well as CD4+ and CD8+ T cells. These studies completed our original Specific Aim 1 and suggested that castration can prime host responses amenable to immunotherapeutic potentiation. Over the last year we have essentially addressed Specific Aims 2 and 3 by showing that androgen ablation can facilitate/potentiate the effectiveness of novel immunotherapies (anti-CD40 and anti-CTLA-4 treatment) to enhance T cell-mediated TRAMP tumor inflammation for prostate cancer treatment. Hence, we have extended our studies by conducting a number of exploratory experiments to elucidate central mechanisms whereby androgen ablation augments host T cell-mediate immunity.