Cancer Cell
Volume 32, Issue 3, 11 September 2017, Pages 377-391.e9
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Article
Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

https://doi.org/10.1016/j.ccell.2017.08.004 Get rights and content
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Highlights

  • Metabolic stress causes CD8+ TIL exhaustion regardless of their antigen specificity

  • Low O2 and glucose induce CD8+ TILs to enhance FA catabolism to preserve functions

  • Promoting FA catabolism of CD8+ TILs improves their ability to combat tumors

  • A PPAR-α agonist enhances the therapeutic effect of PD-1 blockade in melanoma

Summary

How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8+ TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8+ TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8+ TILs' antigen specificity. Further promoting FA catabolism improves the CD8+ TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures.

Keywords

melanoma
tumor microenvironment
CD8+ T cells
TILs
co-inhibitors
hypoxia
HIF-1α
hypoglycemia
fatty acid catabolism
fenofibrate

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Present address: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA

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