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

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.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

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 ST,Valge-Archer VE,Smith PD,Banchereau J,Mkrtichyan M,Youngblood B,Rodriguez PC,Gupta S,Khleif SN

doi

10.1038/s41590-020-00818-9

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

53-66

issue

1

eissn

1529-2908

issn

1529-2916

pii

10.1038/s41590-020-00818-9

journal_volume

22

pub_type

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