PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

By N. Patsoukis, Kankana Bardhan, Pranam Chatterjee, Duygu Sari, Bianling Liu, L. N. Bell, Edward D. Karoly, G. Freeman, V. Petkova, P. Seth and 2 more. Nature Communications, 2015

1,091 citations recorded by the source corpus.

During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade. Activation of T cells results in metabolic reprogramming to favour glycolysis. Here, Patsoukis et al. show that the surface receptor PD-1 inhibits glycolysis and increases the metabolism of lipids, providing a potential mechanism for the blockade of T effector functions but also for the longevity accompanying T cell exhaustion.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/1bd348030f530f71994d9fac0e31e73a528218da

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Citations in the corpus

Bioenergetic insufficiencies due to metabolic alterations regulated by PD-1 are an early driver of CD8+ T cell exhaustion (2016, background): “In vitro, engaging PD-1 or CTLA-4 on activated T cells reduces Akt and mTOR signaling, and suppresses glycolysis (Parry et al., 2005; Patsoukis et al., 2015).”
Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “Although in a separate study, FAO inhibition exhibited delayed tumor growth and enhanced anti-tumor efficacy of T cells (Q. Zhang et al., 2018).”
Metabolic Instruction of Immunity (2017, neutral): “PD-1 not only suppresses TCR, PI3K and mTOR signaling in T cells, but also dampens glycolysis and promotes fatty acid oxidation (FAO) – features that may enhance the accumulation of suppressive regulatory CD4 T (Treg) cells in tumors (Bengsch et al., 2016; Parry et al., 2005; Patsoukis et al., 2015)”
Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, result): “Consistent with this idea and published reports (Parry et al., 2005; Patsoukis et al., 2015; Pedicord et al., 2015; Staron et al., 2014), even treating in vitro activated T cells, which are already highly glycolytic, with PD-1 and CTLA-4 antibodies further slightly increased ECAR (Figures S3B and S3”
Immunosenescence: molecular mechanisms and diseases (2023, background): “As the immune system ages, metabolism undergoes changes that involve increased glycolysis, mitochondrial dysfunction, and reactive oxygen species (ROS).(55,56) These features of immunosenescence are strongly related to high morbidity and mortality from age-associated diseases such as cardiovascular ”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “For example, PD-1 signaling stimulates the over-expression of the rate-limiting enzyme CPT1A in fatty acid oxidation (FAO), leading T cells to rely on FAO over glycolysis as their main source of energy [124].”
T cell metabolism drives immunity (2015, background): “A recent report also found that inhibition of T cell signaling through ligation of PD-1 induces changes in the metabolic profile of activated T cells, including decreased aerobic glycolysis and enhanced FAO (Patsoukis et al., 2015).”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “During T cell activation, ligation of the inhibitory receptor programmed cell death protein 1 (PD-1) sustains FAO and prevents glycolysis induction, decreasing Te cell function (82).”
Cytotoxic CD8+ T cells in cancer and cancer immunotherapy (2020, background): “death.(32) Potentiating TCR signalling by antibody blockade of PD-1 thus restores CD8 T-cell functions.”