Discovery of Small Molecules for the Reversal of T Cell Exhaustion

Abstract

Inhibitory receptors (IRs) function as critical regulators of immune responses by tempering Tcell activity. In humans, several persisting viruses as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of Tcell 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+ Tcell activity. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted Tcells. 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 Tcells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of Tcell function and reveal new targets for immunotherapy.