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


ABSTRACT: 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.

SUBMITTER: Klein Geltink RI 

PROVIDER: S-EPMC10863625 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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CD8<sup>+</sup> effector T (T<sub>E</sub>) 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<sup>+</sup> T<sub>E</sub> cells metabolically primes effector functions and enhances tumour clearance in mice. Tumour-specific TGR CD8<sup>+</sup> T<sub>E</sub> cells co-cultured  ...[more]

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