MEK inhibition reprograms CD8 + T lymphocytes into memory stem cells with potent antitumor effects
Nat Immunol 2021 Jan; 22(1):53-66
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.
Verma, Vivek; Jafarzadeh, Nazli; Boi, Shannon; Kundu, Subhadip; Jiang, Zhinuo; Fan, Yiping; Lopez, Jose; Nandre, Rahul; Zeng, Peng; Alolaqi, Fatmah; Ahmad, Shamim; Gaur, Pankaj; Barry, Simon T; Valge-Archer, Viia E; Smith, Paul D; Banchereau, Jacques; Mkrtichyan, Mikayel; Youngblood, Benjamin; Rodriguez, Paulo C; Gupta, Seema; and Khleif, Samir N, "MEK inhibition reprograms CD8 + T lymphocytes into memory stem cells with potent antitumor effects" (2021). Faculty Research 2021. 2.