MEK inhibition reprograms CD8 + T lymphocytes into memory stem cells with potent antitumor effects
Document Type
Article
Publication Date
1-2021
Keywords
JGM, JAXCC
JAX Source
Nat Immunol 2021 Jan; 22(1):53-66
Volume
22
Issue
1
First Page
53
Last Page
66
ISSN
1529-2916
PMID
33230330
DOI
https://doi.org/10.1038/s41590-020-00818-9
Abstract
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.
Recommended Citation
Verma V,
Jafarzadeh N,
Boi S,
Kundu S,
Jiang Z,
Fan Y,
Lopez J,
Nandre R,
Zeng P,
Alolaqi F,
Ahmad S,
Gaur P,
Barry S,
Valge-Archer V,
Smith P,
Banchereau J,
Mkrtichyan M,
Youngblood B,
Rodriguez P,
Gupta S,
Khleif S.
MEK inhibition reprograms CD8 + T lymphocytes into memory stem cells with potent antitumor effects Nat Immunol 2021 Jan; 22(1):53-66