Identifying autocrine signaling molecules regulating T cell fate decisions 2692

Abstract Description Cancer immunotherapies have drastically improved cancer patient outcomes, yet many patients with solid tumors still do not respond. As such, identifying novel strategies to increase the size and function of the patient’s CD8+ T cell response to solid tumor remains an important goal. Current dogma in cancer immunotherapy focuses on the suppressive signals from the tumor microenvironment received by T cells, but the existence and impact of suppressive factors secreted by CD8+ T cells themselves is incompletely understood. An autocrine CD8+ T cell regulatory axis was recently discovered wherein tumor-specific CD8+ T cells secrete the cytokine fibrinogen-like protein 2 (Fgl2), to induce their apoptosis through binding the inhibitory IgG-Fc receptor, FcγRIIB. This discovery supports the conclusion that CD8+ T cells can actively thwart the T cell response by making their own “off switch” and raises the theoretical prospect that other T cell autocrine regulatory pathways may exist to dampen T cell immunity. To this end, we will study the secretome and spatial transcriptome of CD8+ T cells isolated from the tumors of mice and humans with the goal of identifying novel regulatory receptor-ligand pairs. Further, assessing cell–cell communication networks in a spatial context will enable deeper understanding of the molecular pathways that program T cell responses, knowledge that could be leveraged by T cell-based therapies such as TIL or CAR-T therapy. Funding Sources Supported by NIH/NCI K00CA28425502 to KBB; R01AI06754515 to AG Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)