Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8(+) T cell stemness and antitumor immunity

Fecha de publicación: 17/03/2020

Autores de IIS La Fe

Juan Carlos García Cañaveras

Autor

Participantes ajenos a IIS La Fe

Hermans, D
Gautam, S
Gromer, D
Mitra, S
Spolski, R
Li, P
Christensen, S
Nguyen, R
Lin, JX
Oh, J
Du, N
Veenbergen, S
Fioravanti, J
Ebina-Shibuya, R
Bleck, C
Neckers, LM
Rabinowitz, JD
Gattinoni, L
Leonard, WJ

Grupos

Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Leader

Agustín Lahoz Rodríguez

Abstract

Interleukin (IL)-2 and IL-21 dichotomously shape CD8(+) T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (T-SCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1. While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.

Datos de la publicación

ISSN/ISSNe:: 0027-8424, 1091-6490
Tipo:: Article
Páginas:: 6047-6055
DOI:: 10.1073/pnas.1920413117
Factor de Impacto:: 5,011 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Hermans, D:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Gautam, S:: NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA
Garcia-Canaveras, JC:: Princeton Univ, Dept Chem, Princeton, NJ 08540 USA

Princeton Univ, Lewis Sigler Inst, Princeton, NJ 08540 USA

Instituto de Investigación. Inst Invest Sanitaria Fdn Hosp La Fe, Unidad Biomarcadores & Med Precis, Unidad Analit, Valencia 46026, Spain
Gromer, D:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA
Mitra, S:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

Univ Lille, UMR S 1172 JPARc Ctr Res Jean Pierre Aubert Neuro, F-59000 Lille, France
Spolski, R:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Li, P:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Christensen, S:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

Pfizer, Dept Inflammat & Immunol, Cambridge, MA 02139 USA
Nguyen, R:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Lin, JX:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Oh, J:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Du, N:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Veenbergen, S:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

Erasmus MC, Lab Pediat Gastroenterol, NL-3015 GD Rotterdam, Netherlands
Fioravanti, J:: NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA
Ebina-Shibuya, R:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA
Bleck, C:: NHLBI, Electron Microscopy Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA
Neckers, LM:: NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA
Rabinowitz, JD:: Princeton Univ, Dept Chem, Princeton, NJ 08540 USA

Princeton Univ, Lewis Sigler Inst, Princeton, NJ 08540 USA
Gattinoni, L:: NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

Univ Regensburg, Regensburg Ctr Intervent Immunol, D-93053 Regensburg, Germany

Univ Hosp Regensburg, D-93053 Regensburg, Germany
Leonard, WJ:: NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA

NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA