Anti-Tumor Mechanisms of Intratumoral Stimulatory Dendritic Cells

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Project Summary/Abstract Treating the immune response within tumors is a major focus of new therapeutic development. Much of the focus has been place on T cells, in particular via checkpoint therapies such as anti-CTLA4 or anti-PD1. Little is currently known of how individual populations of myeloid cells can be partners for T cells. We have recently isolated rare populations of myeloid cells that appear critical for robust responses but we don't yet fully understand how they work. We hypothesize that rare stimulatory dendritic cells traffic antigens and stimulate T cell according to specialized rules and that harnessing and modulation of this pathway is part of the reason that checkpoint blockades may work. We further hypothesize that specific tissue-based cells are responsible for upregulating the critical cytokine to make stimulatory dendritic cells but that tissue production is dysregulated in cancer and possibly improved with checkpoint therapies. In this proposal we will be vastly extending an approach that my lab has been pursuing over the last few years. Specifically we will be extending our cell-biology based studies of these critical cells (Aim1) to understand how they play a fundamental role in antigen trafficking. Additionally, we will seek to understand how they hand off antigen to other antigen-presenting cells in the lymph node to engage T cells (Aim2) and how both of these processes are affected by checkpoint blockades. Finally, in aim 3, we will seek to understand the normal and intratumoral production of the cytokine Flt3L, a key player in regulating the number of these rare cells. At the end of this work, we will understand how these intratumoral myeloid cells function on their own and in concert with T cell therapies.