Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy.

CD8+ effector T (TE) cell proliferation and cytokine production depends on enhanced glucose metabolism. However, circulating T cells continuously adapt to glucose fluctuations caused by diet and inter-organ metabolite exchange. Here we show that transient glucose restriction (TGR) in activated CD8+ TE cells metabolically primes effector functions and enhances tumour clearance in mice. Tumour-specific TGR CD8+ TE cells co-cultured with tumour spheroids in replete conditions display enhanced effector molecule expression, and adoptive transfer of these cells in a murine lymphoma model leads to greater numbers of immunologically functional circulating donor cells and complete tumour clearance. Mechanistically, TE cells treated with TGR undergo metabolic remodelling that, after glucose re-exposure, supports enhanced glucose uptake, increased carbon allocation to the pentose phosphate pathway (PPP) and a cellular redox shift towards a more reduced state-all indicators of a more anabolic programme to support their enhanced functionality. Thus, metabolic conditioning could be used to promote efficiency of T-cell products for adoptive cellular therapy.

Citation

Ramon I Klein Geltink, Joy Edwards-Hicks, Petya Apostolova, David O'Sullivan, David E Sanin, Annette E Patterson, Daniel J Puleston, Nina A M Ligthart, Joerg M Buescher, Katarzyna M Grzes, Agnieszka M Kabat, Michal Stanczak, Jonathan D Curtis, Fabian Hässler, Franziska M Uhl, Mario Fabri, Robert Zeiser, Edward J Pearce, Erika L Pearce. Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy. Nature metabolism. 2020 Aug;2(8):703-716

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PMID: 32747793

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