Determining the role of intratumoral dendritic cells in anti-tumor immunity

H. Lee Moffitt Cancer Ctr & Res Inst, Tampa FL

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Abstract

PROJECT SUMMARY Conventional dendritic cells (cDCs) are central regulators of the adaptive immune response, and as such are necessary for T cell-mediated cancer immunity. In particular, anti-tumoral responses are induced by a specialized subset of cDCs (cDC1) that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. Less clear is the role of cDCs within the tumor microenvironment, but in general these intratumoral cDCs have been described as immature, tolerogenic, or even immunosuppressive, suggesting that the functionality of cDCs may be a critical barrier to sustaining cytotoxic T cell responses. We have recently described expression of TIM-3 (T-cell immunoglobulin and mucin domain containing-3) on cDCs in human and murine mammary tumors, and found that treatment with ?TIM-3 antibodies improved response to standard-of-care paclitaxel chemotherapy in murine models of triple- negative and luminal B disease. This improved response was dependent upon CD8+ T cells, despite the near absence of TIM-3 expression on this population either prior to or during therapy. However, gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, leading to the central hypothesis for this proposal that TIM-3 blockade can indirectly promote cytotoxic T cell activity by enhancing cDC functionality. In order to address this hypothesis, I propose to determine how TIM-3 blockade alters the activation/functional state of cDC1s (Aim 1) and determine the functional relevance of cDC1s during TIM-3 blockade (Aim 2). As early phase clinical trials combining PD-1 and TIM-3 blocking antibodies have not shown improved efficacy, results from these studies may help determine how TIM-3 blocking antibodies should optimally be utilized in the clinic. !