Tumor-expressed wnts and dendritic cell tolerance in cancer immune evasion

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DESCRIPTION (provided by applicant): A relationship between dendritic cell (DC) tolerance and tumor immune evasion has been established; however, the effector molecules and mechanisms that control the balance of tolerogenic vs immune stimulatory DC function in the tumor environment are incompletely understood. In this proposal I hypothesize that wnt proteins, which are upregulated in many human cancers, can act directly on DCs to promote tolerance, and that the wnt-dependent DC tolerogenic responses contribute to tumor immune evasion. In an effort to address these hypotheses I will determine how tumor-expressed wnts influence DC phenotype and immune function, and will test the role of DC-specific wnt signaling in tumor immune evasion. First, DCs isolated from mouse lymph nodes will be treated with recombinant canonical (wnt3a) or non-canonical wnts (wnt5a), and DC maturation marker expression, cytokine production, and Treg phenotype induction will be assessed. Wnt signaling events in DCs will be elucidated to determine key effector molecules involved in wnt-induced DC tolerance. Second, mice with a targeted dendritic cell-specific deficiency in canonical wnt signaling (DC-specific ß-catenin deletion) will be used to determine the role of DC programming by tumor-expressed wnts in the anti- tumor response. Tumors transduced with wnt-encoding or control vectors will be used. Tumor infiltrating lymphocyte populations, induction of tumor immunity, and immune effects on tumor growth will be compared in the DC-specific ß-catenin deficient vs control mice. The findings from this proposal will define the role and elucidate mechanisms of wnt regulation of the DC tolerogenic phenotype, and will critically test the hypothesis that the tolerogenic effect of tumor-expressed wnts on dendritic cells can be a significant mechanism for tumor immune evasion. Such insights would suggest that targeting tumor-expressed wnt proteins could contribute to immunologic approaches to tumor therapy.