Inhibition of the Protein Tyrosine Phosphatase, SHP-1, in Dendritic Cells to Enhance their Efficacy as Cell-Based Prostate Cancer Vaccines

摘要

Early preclinical and clinical trials suggest that dendritic cell (DC)-based tumor vaccines are both feasible and safe. However, to date clinical trials of DC-based vaccines have demonstrated only limited efficacy in causing tumorregression despite eliciting measurable systemic T cell responses against prostate cancer. In an effort to enhance the effectiveness of DC-based vaccines against prostate cancer, we have tested the hypothesis that the Src homology region 2 domain-containing phosphatase-1 (SHP-1), is a global inhibitor of DC activation and that by blocking SHP-1 in DC would induce stronger anti-tumor immunity. Our results demonstrate that inhibition of SHP-1 enhances DC activation, survival and migration in vitro. Further, using in vivo mouse models, we show that SHP-1 inhibition in DC enhances the generation of CD8+ effector T cells and skews the CD4+ T cell compartment to a Th1 phenotype while inhibiting the induction of T regulatory cells. These observations suggest that SHP-1 is a pleiotropic inhibitor of DC function and that its inhibition in DCs enhances the strength of immune responses. Finally, using 2 ectopic mouse tumor models (B16 melanoma and TRAMP prostate tumors), we show that SHP-1 inhibition in DC based vaccines significantly inhibits tumor growth. The implication of these data in concert, is that SHP-1 signaling is a feasible protein to target in the design and implementation of DC-based vaccines against tumors and potentially against other infectious diseases.