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Enhancing CD8 T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. | LitMetric

AI Article Synopsis

  • Tumor-infiltrating T lymphocytes (TILs) adapt to the challenging conditions of the tumor microenvironment, particularly during low glucose and low oxygen levels.
  • In mouse melanoma models, CD8 TILs boost fatty acid catabolism through PPAR-α signaling, which helps maintain their effectiveness against tumors; however, inhibitory proteins also increase as cancer progresses.
  • Combining PD-1 blockade with enhanced fatty acid catabolism in TILs leads to better tumor control and can even result in complete cures.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751418PMC
http://dx.doi.org/10.1016/j.ccell.2017.08.004DOI Listing

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