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.
Breast cancer is the most commonly diagnosed cancer among women in the United States, meaning that identifying effective therapies and improving upon current standard-of-care treatment options is critically important. The research conducted during the F99 phase will explore how the function of dendritic cells is altered during TIM-3 blockade, while the K00 phase will focus on understanding how the location of immune cells within the tumor affects the induction of anti-tumor immunity. Both of these studies will increase our understanding of the mechanisms behind the anti-tumor immune response, and have the potential to inform the design of future immunotherapeutic interventions.
