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515 Metabolic reprogramming of antitumor CD8+ T cell immunity
  1. Alison Jaccard1,
  2. Mathias Wenes1,
  3. Gábor Gyülvészi2,
  4. Ping-Chih Ho1 and
  5. Pedro Romero1
  1. 1UNIL, Epalinges, Switzerland
  2. 2Roche Innovation Center Zurich, Zurich, Switzerland


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.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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