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Series GSE143903 Query DataSets for GSE143903
Status Public on Feb 13, 2020
Title Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design RNA-Seq analyses using TCR pre-activated CD8+ T cells that were treated with either no cytokine, or with IL-2, IL-21, IL-2 + LDHi, IL-21 + LDHi.
 
Contributor(s) Hermans D, Gautam S, García-Cañaveras JC, Gromer D, Mitra S, Spolski R, Li P, Christensen S, Nguyen R, Lin J, Oh J, Du N, Veenbergen S, Fioravanti J, Ebina-Shibuya R, Bleck C, Neckers LM, Rabinowitz JM, Gattinoni L, Leonard WJ
Citation(s) 32123114, 37922339
Submission date Jan 17, 2020
Last update date Feb 13, 2024
Contact name Peng Li
E-mail(s) peng.li@nih.gov
Organization name NIH
Department NHLBI
Lab LMI
Street address 9000 Rockville Pike
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
 
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (10)
GSM4276526 RNA-Seq CD8T NC rep1
GSM4276527 RNA-Seq CD8T IL2 rep1
GSM4276528 RNA-Seq CD8T IL21 rep1
Relations
BioProject PRJNA602006
SRA SRP242645

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Supplementary file Size Download File type/resource
GSE143903_RAW.tar 5.8 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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