Targeting the Epigenome to Improve Responses to Immunotherapy

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Project Summary Conventional dendritic cells (cDCs) are central regulators of the adaptive immune response, and have been shown to be required for the induction of T cell-mediated anti-tumor immunity. In particular, a subset of cDCs (cDC1) is responsible for transporting tumor antigens to the lymph node and cross presenting antigen in order to activate cytotoxic T lymphocytes, thereby inducing an anti-tumor response. We have recently observed TIM- 3 (T-cell immunoglobulin and mucin domain containing-3) expression on cDCs in human and murine mammary tumors, and found that TIM-3 blockade improved response to standard-of-care paclitaxel chemotherapy in models of triple-negative and luminal B disease. This occurred through increased chemokine expression by cDCs, without a corresponding in T cell infiltration, leading me to hypothesize that the spatial localization of cDCs and T cells within tumors is a critical determinant of successfully immunotherapy. In the F99 portion of this application I will therefore seek to determine if TIM-3 blockade alters the spatial organization of T cells, and if this is responsible for therapeutic efficacy. In the K00 phase of this proposal I will expand these studies to evaluate whether cDC/T cell clustering is a prerequisite for response to immune checkpoint blockade and other therapeutic modalities.