PLX313582

GSE156506: Disturbed mitochondrial dynamics in CD8+ TIL reinforce epigenetic programming linked with T cell exhaustion [RNA-Seq]

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Hana Imrichova (hana.imrichova@gmail.com, himrichova@cemm.oeaw.ac.at) - CeMM, Vienna