Discovery of Small Molecules for the Reversal of T Cell Exhaustion

Publication date: 3 December 2019Source: Cell Reports, Volume 29, Issue 10Author(s): Brett S. Marro, Jaroslav Zak, Reza Beheshti Zavareh, John R. Teijaro, Luke L. Lairson, Michael B.A. OldstoneSummaryInhibitory receptors (IRs) function as critical regulators of immune responses by tempering T cell activity. In humans, several persisting viruses as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. Here, we report the design, implementation, and results of a phenotypic high-throughput screen for molecules that modulate CD8+ T cell activity. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted T cells. Analysis of our top hit, ingenol mebutate, a protein kinase C (PKC) inducing diterpene ester, reveals a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of T cell function and reveal new targets for immunotherapy.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research

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