Background Adoptive cell transfer (ACT) therapies are successfully used in the clinic; however, a large fraction of patients remains unresponsive. The limited efficacy of this therapy is due, in part, to the terminally differentiated state of transferred T cells, which limits their proliferation and long-lasting antitumor response. Memory CD8+ T cells display specific phenotypic and functional characteristics endowing them with the ability to provide a more robust and long-lasting antitumor immune response than their terminally differentiated counterparts. The development and fitness of memory T cells was recently shown to be associated with specific metabolic pathways.
Methods We aimed to metabolically reprogram CD8+ T cells in order to generate fitter memory-like T cells prior to ACT.
Results We have found that pharmacological inhibition of the metabolic enzyme isocitrate dehydrogenase 2 (IDH2) during the priming of CD8+ T cells led to an increased memory formation and to an enhanced tumor growth inhibition upon ACT into melanoma tumor-bearing mice. Interestingly, IDH2 inhibition was associated with increased histone methylation and acetylation. We show that these histone modifications were required to induce the observed memory phenotype.
Conclusions These results suggest a novel strategy to promote stable memory T cell differentiation by epigenetic processes induced by metabolic reprogramming during T cell priming. These findings might be exploited to optimize ACT immunotherapy against cancer.
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