MEK inhibition reprograms CD8

Vivek Verma
Nazli Jafarzadeh
Shannon Boi
Subhadip Kundu
Zhinuo Jiang
Yiping Fan
Jose Lopez
Rahul Nandre
Peng Zeng
Fatmah Alolaqi
Shamim Ahmad
Pankaj Gaur
Simon T Barry
Viia E Valge-Archer
Paul D Smith
Jacques Banchereau, The Jackson Laboratory
Mikayel Mkrtichyan
Benjamin Youngblood
Paulo C Rodriguez
Seema Gupta
Samir N Khleif


Regenerative stem cell-like memory (TSCM) CD8+ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces TSCM 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 TSCM cells exhibited plasticity and loci-specific profiles similar to bona fide TSCM 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 TSCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.