| First Author | Marro BS | Year | 2019 |
| Journal | Cell Rep | Volume | 29 |
| Issue | 10 | Pages | 3293-3302.e3 |
| PubMed ID | 31801090 | Mgi Jnum | J:301682 |
| Mgi Id | MGI:6489178 | Doi | 10.1016/j.celrep.2019.10.119 |
| Citation | Marro BS, et al. (2019) Discovery of Small Molecules for the Reversal of T Cell Exhaustion. Cell Rep 29(10):3293-3302.e3 |
| abstractText | Inhibitory 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. |
