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

Dalton Hermans, Sanjivan Gautam, Juan C. García-Cañaveras, Daniel Gromer, Suman Mitra, Rosanne Spolski, Peng Li, Stephen Christensen, Rosa Nguyen, Jian Xin Lin, Jangsuk Oh, Ning Du, Sharon Veenbergen, Jessica Fioravanti, Risa Ebina-Shibuya, Christopher Bleck, Leonard M. Neckers, Joshua D. Rabinowitz, Luca Gattinoni, Warren J. Leonard

Research output: Contribution to journalArticle

2 Scopus citations

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 (TSCM) 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.

Original languageEnglish (US)
Pages (from-to)6047-6055
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number11
DOIs
StatePublished - Mar 17 2020

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Adoptive immunotherapy
  • IL-2
  • IL-21
  • Immunometabolism
  • LDH

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    Hermans, D., Gautam, S., García-Cañaveras, J. C., Gromer, D., Mitra, S., Spolski, R., Li, P., Christensen, S., Nguyen, R., Lin, J. X., Oh, J., Du, N., Veenbergen, S., Fioravanti, J., Ebina-Shibuya, R., Bleck, C., Neckers, L. M., Rabinowitz, J. D., Gattinoni, L., & Leonard, W. J. (2020). Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity. Proceedings of the National Academy of Sciences of the United States of America, 117(11), 6047-6055. https://doi.org/10.1073/pnas.1920413117