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 Gupta; Samir N. Khleif

doi:10.1038/s41590-020-00818-9

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 journal › Article › peer-review

101 Scopus citations

Abstract

Regenerative stem cell–like memory (T_SCM) CD8⁺ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T_SCM 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 T_SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T_SCM 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 T_SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.

Original language	English (US)
Pages (from-to)	53-66
Number of pages	14
Journal	Nature immunology
Volume	22
Issue number	1
DOIs	https://doi.org/10.1038/s41590-020-00818-9
State	Published - Jan 2021
Externally published	Yes

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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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-020-00818-9

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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. T., Valge-Archer, V. E., Smith, P. D., Banchereau, J., Mkrtichyan, M., Youngblood, B., Rodriguez, P. C., ... Khleif, S. N. (2021). MEK inhibition reprograms CD8⁺ T lymphocytes into memory stem cells with potent antitumor effects. Nature immunology, 22(1), 53-66. https://doi.org/10.1038/s41590-020-00818-9

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 2021, 'MEK inhibition reprograms CD8⁺ T lymphocytes into memory stem cells with potent antitumor effects', Nature immunology, vol. 22, no. 1, pp. 53-66. https://doi.org/10.1038/s41590-020-00818-9

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title = "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.",

author = "Vivek Verma and Nazli Jafarzadeh and Shannon Boi and Subhadip Kundu and Zhinuo Jiang and Yiping Fan and Jose Lopez and Rahul Nandre and Peng Zeng and Fatmah Alolaqi and Shamim Ahmad and Pankaj Gaur and Barry, {Simon T.} and Valge-Archer, {Viia E.} and Smith, {Paul D.} and Jacques Banchereau and Mikayel Mkrtichyan and Benjamin Youngblood and Rodriguez, {Paulo C.} and Seema Gupta and Khleif, {Samir N.}",

note = "Funding Information: We are grateful to Jeannie and Tony Loop for their generous support to SNK{\textquoteright}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: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Verma, Vivek

AU - Jafarzadeh, Nazli

AU - Boi, Shannon

AU - Kundu, Subhadip

AU - Jiang, Zhinuo

AU - Fan, Yiping

AU - Lopez, Jose

AU - Nandre, Rahul

AU - Zeng, Peng

AU - Alolaqi, Fatmah

AU - Ahmad, Shamim

AU - Gaur, Pankaj

AU - Barry, Simon T.

AU - Valge-Archer, Viia E.

AU - Smith, Paul D.

AU - Banchereau, Jacques

AU - Mkrtichyan, Mikayel

AU - Youngblood, Benjamin

AU - Rodriguez, Paulo C.

AU - Gupta, Seema

AU - Khleif, Samir N.

N1 - 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.

PY - 2021/1

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N2 - 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.

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