MEK inhibition reprograms CD8 T lymphocytes into memory stem cells with potent antitumor effects.

Regenerative stem cell-like memory (T) CD8 T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T cells exhibited plasticity and loci-specific profiles similar to bona fide T isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8 T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8 T cell reprogramming into T that acts as a reservoir for effector T cells with potent therapeutic characteristics.