Enhancing the Efficacy of Prostate Cancer Immunotherapy by Manipulating T-Cell Receptor Signaling in Order to Alter Peripheral Regulatory T-Cell Activity

摘要

Immunotherapeutic strategies are a novel treatment option for incurable late-stage and metastatic prostate cancer. Several prostate-related antigens have been identified and even used clinically in therapeutic vaccine strategies, but the results have been disappointing. The activity of CD4+CD25+FOXP3+ regulatory T cells (Tregs) is a mechanism of peripheral tolerance that regulates immune responses, including those induced by therapeutic vaccination against cancer-associated antigens. PEST-domain enriched tyrosine phosphatase (PEP) is a critical negative regulator of the strength of TCR signaling in the thymus, which in turn has a central role in the development of regulatory T cells. Knockout of PEP leads to an increased number of peripheral Tregs. Thus, it was expected that transgenic mice harboring a gain-of-function variant of the human ortholog of PEP (called LYP) would have fewer peripheral Tregs, but this study has revealed that this is not the case. In response to this unexpected finding, an alternative breeding and research strategy was executed involving the novel depletion of Treg (DEREG) mouse model, completing Specific Aim 1. Using these mice, it has been demonstrated that the efficacy of therapeutic immunotherapy is significantly reduced as prostate cancer advances, and that regulatory T cells have a role in limiting vaccine effectiveness. Overall, these data indicate the crucial role of Tregs in limiting the efficacy of therapeutic cancer vaccines, and highlight the urgent need to develop specific pharmacological means by which to inhibit these cells in humans.