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

Nat Metab. 2020 Aug;2(8):703-716. doi: 10.1038/s42255-020-0256-z. Epub 2020 Aug 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods*
  • Animals
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / transplantation*
  • Carbon / metabolism
  • Cell Line
  • Cytokines / biosynthesis
  • Glucose / deficiency
  • Glucose / pharmacology
  • Immunologic Memory
  • Lymphocyte Activation
  • Lymphoma / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Pentose Phosphate Pathway
  • Reactive Oxygen Species / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Cytokines
  • Reactive Oxygen Species
  • Carbon
  • Glucose