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

Stem cell-like memory (T-SCM) CD8(+) T cells are beneficial in antitumor responses, in part due to their ability to self-renew. Khleif and colleagues demonstrate that inhibition of the kinase MEK in CD8(+) T cells favors induction of T-SCM and superior antitumor responses. Regenerative stem cell-like memory (T-SCM) CD8(+) T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T-SCM 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-SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T-SCM 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-SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.