One major obstacle for the success of dendritic cell (DC) vaccines is host DC-mediated immunosuppression. Cross-priming, a process which DCs activate CD8+ T cells through cross-presentation, plays a major role in generating anti-tumor CD8+ T cell immunity. Tumor antigen cross-presentation by host DCs, however, often induces CD8+ T cell tolerance instead of immunity. Thus, there is a critical need to better understand whether and how tumors modulate cross-priming to suppress CD8+ T cell immunity. The long-term goal is to develop strategies to block tumor-induced immunosuppression to augment CD8+ T cell immunity and improve cancer vaccine efficacy. The objectives in this application is to elucidate the underlying mechanisms of how tumors inhibit cross-priming through ?-catenin in DCs, and validate blocking ?-catenin signaling as a novel strategy to improve cancer vaccine efficacy. The central hypothesis is that tumors differentially regulate DCs' cytokine induction through ?-catenin to inhibit cross-priming, and blocking ?-catenin's function in cross-priming augments vaccine-induced anti-tumor CD8+ T cell immunity. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratory. The rationale is that once it is known how tumors suppress CD8+ T cell responses through ?-catenin, strategies targeting ?-catenin signaling can then be developed to improve cancer vaccine efficacy.
Three specific aims are proposed: 1) To determine whether activation of ?-catenin in DCs suppresses anti- tumor CD8+ T cell immunity under diverse cancer vaccinations. 2) To elucidate the molecular mechanisms of how tumors inhibit cross-priming through ?-catenin in DCs. 3) To determine whether blocking ?-catenin pharmacologically improves cancer vaccine efficacy. We will carry out adoptive transfer, phenotypic and functional assays including multiple cross-priming assays, real-time PCR, in vivo killing assays and DC-targeted vaccinations with DC-specific knockout mice with either active or inactive ?-catenin. The project is innovative because: (1) Based on the findings that ?-catenin mediates tumor-induced suppression of CD8+ T cell immunity by inhibiting cross-priming, we will determine whether a novel strategy targeting DCs' function in cross-priming improves vaccine efficacy. (2) Using genetic and pharmacological approaches to alter ?-catenin expression, this proposal will elucidate the mechanisms of how tumors inhibit cross-priming through ?-catenin in DCs. As ?- catenin inhibitors have been tested in pre-clinical studies and clinical trials, this proposal will additionally provide direct evidence to support the application of ?-catenin inhibitors in cancer vaccines. The proposed research is significant, because it addresses how cross-priming is modulated by tumors to achieve DC-mediated immunosuppression, a fundamental but unanswered question in cancer immunology and DC biology, and more importantly will validate modulating ?-catenin signaling as a novel strategy to improve cancer vaccine efficacy.
The proposed studies are relevant to public health for two reasons. First, they will provide the critical information on the mechanisms of how anti-tumor CD8+ T cell immunity is suppressed by tumors. Secondly, they will provide the proof-of-concept of novel strategies to enhance DC vaccine-induced CD8+ T cell immunity to improve efficacy of cancer vaccines. Thus the proposed research is relevant to the part of NCI's mission on cancer research.
