Abstract
Abstract Head and neck squamous cell carcinomas (HNSCC) are aggressive cancers that are associated with high morbidity and mortality. Anti-tumor immune responses rely on the ability of cytotoxic T and NK cells to infiltrate the solid tumor microenvironment and kill the cancer cells. However, solid tumors utilize multiple mechanisms to evade these cells including the production of exosomes, which inhibit immune cell function and present a major block to immunotherapy. The mechanisms by which the tumor-derived exosomes (TEX) inhibit immune cell functionality are poorly understood. We isolated TEX from a HNSCC patient tumor-derived primary cancer cell line by ultracentrifugation and characterized them by electron microscopy and flow cytometry. We exposed healthy donor (HD) peripheral blood mononuclear cells (PBMCs) to TEX, followed by activation, and conducted preliminary single-cell studies by measuring transcriptome (NanoString), secretome of 32 secreted proteins (Isoplexis) and immune cell function (electrophysiology). Transcriptomic studies revealed that TEX reduced the abundance of cytotoxic cells, and inhibited immune responses associated with cytotoxicity, chemokines, and NK and T cell functions. In CD8 +T and NK cells, TEX reduced polyfunctionality (the ability to secrete multiple cytokines from a single cell). ELISA showed that TEX reduced IFN-γ secretion by CD8 +T and NK cells. KCa3.1 channels regulate the Ca 2+signaling necessary for these immune effector functions, but the effect of TEX on KCa3.1 activity is not known. Electrophysiology revealed that TEX inhibited KCa3.1 channel activity in HD CD8 +T cells. Overall, our data suggest that KCa3.1 channels mediate the inhibitory effect of TEX on anti-tumor immunity. Bridge funds by the Dept of Internal Medicine, University of Cincinnati to Dr. Laura Conforti Pilot grant from the University of Cincinnati Cancer Center to Dr. Laura Conforti
Published Version
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