Reversible mitochondrial dysfunction drives terminal T-cell exhaustion
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ABSTRACT:
PROVIDER: PRJNA575910 | ENA |
REPOSITORIES: ENA
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Project description:The failure of T-cells to control tumor growth has been associated with several functional defects that collectively lead to T-cell “exhaustion.” This phenotype results from chronic antigen stimulation within the tumor microenvironment, but how repetitive antigenic stimulation leads to T-cell exhaustion remains poorly defined. Here we show that persistent antigen stimulation induces mitochondrial oxidative stress that reduces tricarboxylic acid (TCA) cycle activity. The resultant bioenergetic compromise impairs nucleotide triphosphate synthesis, induces endoplasmic reticulum (ER) stress, and activates an exhaustion-associated gene expression program. Reversal of oxidative stress with N-acetylcysteine effectively restores T-cell proliferation, effector function, and memory-associated gene expression and enhances anti-tumor T-cell efficacy in vivo. These data reveal that induction of mitochondrial oxidative stress is a critical component of terminal T-cell dysfunction. Furthermore, treatments that restore mitochondrial redox are sufficient to prevent T-cell exhaustion and enhance anti-tumor immunity.
2020-05-21 | GSE138459 | GEO
Project description:Interventions: Gold Standard:Comparison methods :(1) comparison of similar kits;(2) Sequencing method;Index test:Human 13 gene mutation Combination Detection Kit (reversible terminal termination sequencing method)
Primary outcome(s): Lung and gastrointestinal tumor genes
Study Design: Sequential
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Project description:The metabolic challenges present in tumors attenuate the metabolic fitness and anti-tumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulating depolarized mitochondria as a result of declined mitophagy activity display functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, declined mitochondrial fitness in TILs is induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signal. Forcing the accumulation of depolarized mitochondria with pharmacological interventions induces epigenetic reprogramming for terminal exhaustion, indicating that mitochondrial deregulation is indeed a cause – rather than a consequence – of T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal new insights on how mitochondrial dynamics and quality orchestrate T cell anti-tumor responses and commitment to the exhaustion program.
2020-09-01 | GSE144582 | GEO
Project description:The metabolic challenges present in tumors attenuate the metabolic fitness and anti-tumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulating depolarized mitochondria as a result of declined mitophagy activity display functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, declined mitochondrial fitness in TILs is induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signal. Forcing the accumulation of depolarized mitochondria with pharmacological interventions induces epigenetic reprogramming for terminal exhaustion, indicating that mitochondrial deregulation is indeed a cause – rather than a consequence – of T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal new insights on how mitochondrial dynamics and quality orchestrate T cell anti-tumor responses and commitment to the exhaustion program.
2020-09-01 | GSE144583 | GEO
Project description:Natural Killer (NK) cells often become dysfunctional during tumor progression but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up new mouse lymphoma models activating or not NK cells. Both tumor types elicited IFN-I production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Additionally, ICP positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from the induction of ICPs, which occurred as a later event during tumor growth. Finally, NK cell responsiveness was restored when stimulation was discontinued, and IL-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled, and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs
2024-04-19 | GSE264063 | GEO
Project description:The metabolic challenges present in tumors attenuate the metabolic fitness and anti-tumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulating depolarized mitochondria as a result of declined mitophagy activity display functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, declined mitochondrial fitness in TILs is induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signal. Forcing the accumulation of depolarized mitochondria with pharmacological interventions induces epigenetic reprogramming for terminal exhaustion, indicating that mitochondrial deregulation is indeed a cause – rather than a consequence – of T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal new insights on how mitochondrial dynamics and quality orchestrate T cell anti-tumor responses and commitment to the exhaustion program.
2020-09-01 | GSE156506 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136891 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136853 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136796 | GEO
Project description:Tacrolimus- and sirolimus-induced human b cell dysfunction is reversible and preventable
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