期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 11, 页码 6047-6055出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1920413117
关键词
IL-2; IL-21; LDH; adoptive immunotherapy; immunometabolism
资金
- Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI)
- Division of Intramural Research, National Cancer Institute
- NIH [R01 CA163591, DP1DK113643]
- European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie Grant [751423]
- NIH Medical Research Scholars Program
- MSD Life Science Foundation
- NATIONAL CANCER INSTITUTE [ZIABC010683] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZICHL005906, ZIAHL005402, ZIAHL005401, ZIAHL005408] Funding Source: NIH RePORTER
- Marie Curie Actions (MSCA) [751423] Funding Source: Marie Curie Actions (MSCA)
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.
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