Tumor Vaccination: Modulation of Inhibitory Signaling in Antigen-presenting cells

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DESCRIPTION (provided by applicant): An effective tumor vaccine is required to induce antigen-specific responses that are able to overcome tumor-mediated immune suppression. Dendritic cells (DCs) play a critical role in the initiation and maintenance of immune response and are regulated by stimulatory as well as inhibitory signaling. Our recent studies demonstrate that the antigen presentation capacity of DCs and the magnitude of adaptive immunity are critically controlled by the suppressor of cytokine signaling 1 (SOCS1) in DCs, and SOCS1-silenced DCs are hyperactivated and have an enhanced immunostimulatory capacity to induce antigen- specific CTL responses. The goal of this study is to develop a novel immunization strategy to overcome tumor-mediated immunosuppression by inhibiting a cytokine signaling inhibitor in DCs. The central hypothesis of this study is that silencing SOCS1 allows unbridled pro-inflammatory STATs signaling to antagonize anti-inflammatory STATS signaling in DCs, leading to the overcoming of tumor-mediated immune suppression and induction of effective antitumor responses. The specific aims of this study are: Aim 1). To test the hypothesis that SOCS1 silencing in DCs will allow unbridled pro-inflammatory STATs signaling to antagonize tumor-derived factors-mediated anti-inflammatory STAT3 signaling, leading to the overcoming of tumor-mediated immune suppression and induction of effective antitumor responses. Aim 2). To test the hypothesis that self-reactive CTLs that are persistently activated by SOCS1-silenced, hyperactivated DCs in tumor-bearing mice are resistant to tumor immunosuppression. Aim 3). To test the hypothesis that SOCS1-silenced, hyperactivated DCs in the tumor environment can induce a long- term CTL response against self TRP2. The significance of this study is twofold: first, this study will lead to the development of novel tumor vaccines capable of overcoming tumor-mediated immunosuppression and breaking self tolerance by disabling signaling inhibitors such as SOCS1 in DCs; and second, this study contributes to elucidating the mechanisms that regulate T-cell activation and antigen-presentation by DCs in the tumor environment.