MEK inhibition reprograms CD8+ T lymphocytes into memory stem cells with potent antitumor effects.
Vivek VermaNazli JafarzadehShannon K BoiSubhadip KunduZhinuo JiangYiping FanJose LopezRahul NandrePeng ZengFatmah AlolaqiShamim AhmadPankaj GaurSimon T BarryViia E Valge-ArcherPaul D SmithJacques F BanchereauMikayel MkrtichyanBenjamin A YoungbloodPaulo C RodriguezSeema GuptaSamir N KhleifPublished in: Nature immunology (2020)
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.
Keyphrases
- cell therapy
- stem cells
- dna methylation
- working memory
- mesenchymal stem cells
- single cell
- fatty acid
- induced apoptosis
- dendritic cells
- regulatory t cells
- oxidative stress
- gene expression
- pi k akt
- hiv infected
- adipose tissue
- cell cycle arrest
- insulin resistance
- type diabetes
- anti inflammatory
- drug induced
- nitric oxide
- skeletal muscle
- high fat diet induced
- bone marrow
- metabolic syndrome
- high glucose