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

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, Mikayel Mkrtichyan, Benjamin Youngblood, Paulo C. Rodriguez, Seema GuptaSamir N. Khleif

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)53-66
Number of pages14
JournalNature immunology
Volume22
Issue number1
DOIs
StatePublished - Jan 2021
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to Jeannie and Tony Loop for their generous support to SNK’s laboratory. We acknowledge the Georgia Cancer Center, Augusta University internal support grant to S.N.K. and Flow Cytometry Core Facility at Lombardi Comprehensive Cancer Center. We acknowledge the Metabolomics and Flow Cytometry/Cell Sorting Shared Resource in Georgetown University, which is partially supported by NIH/NCI/CCSG grant P30-CA051008 and NIH S10 grant S10OD016213. We thank S. Bansal for technical assistance with LC–MS data acquisition and S. Li for LC–MS data processing and analysis. This study was supported in part by NIH grant 1 R01 CA237311 01A1 to B.Y. and NIH grants R01-CA184185, R01-CA233512 and P30-CA076292 and The Florida Department of Health grant no. 20B04 to P.C.R. We acknowledge the contribution of P. Finger from the electron microscopy service at the Jackson Laboratory for assistance with electron microscopy.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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