Enhancing CD8 T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Author Ying Zhang, Raj Kurupati, Ling Liu, Xiang Zhou, Gao Zhang, Abeer Hudaihed, Flavia Filisio, Wynetta Giles-Davis, Xiaowei Xu, Giorgos Karakousis, Lynn Schuchter, Wei Xu, Ravi Amaravadi, Min Xiao, Norah Sadek, Clemens Krepler, Meenhard Herlyn, Gordon Freeman, Joshua Rabinowitz, Hildegund Ertl Publication Year 2017 Type Journal 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. Keywords Stress, Physiological, Animals, Humans, Fatty Acids, Mice, Inbred C57BL, Glucose, Oxygen, Female, Tumor Microenvironment, Gene Knockdown Techniques, Treatment Outcome, Disease Progression, Immunotherapy, Lymphocyte Activation, Cell Hypoxia, CD8-Positive T-Lymphocytes, Melanoma, Antigens, CD, Hypoxia-Inducible Factor 1, alpha Subunit, Lymphocytes, Tumor-Infiltrating, Programmed Cell Death 1 Receptor, Lymphocyte Activation Gene 3 Protein Journal Cancer Cell Volume 32 Issue 3 Pages 377-391.e9 Date Published 2017 Sep 11 ISSN Number 1878-3686 DOI 10.1016/j.ccell.2017.08.004 Alternate Journal Cancer Cell PMCID PMC5751418 PMID 28898698 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML