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

TitleEnhancing CD8 T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy.
Publication TypeJournal Article
Year of Publication2017
AuthorsZhang, Y, Kurupati, R, Liu, L, Zhou, XYang, Zhang, G, Hudaihed, A, Filisio, F, Giles-Davis, W, Xu, X, Karakousis, GC, Schuchter, LM, Xu, W, Amaravadi, R, Xiao, M, Sadek, N, Krepler, C, Herlyn, M, Freeman, GJ, Rabinowitz, JD, Ertl, HCJ
JournalCancer Cell
Volume32
Issue3
Pagination377-391.e9
Date Published2017 09 11
ISSN1878-3686
KeywordsAnimals, Antigens, CD, CD8-Positive T-Lymphocytes, Cell Hypoxia, Disease Progression, Fatty Acids, Female, Gene Knockdown Techniques, Glucose, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunotherapy, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Melanoma, Mice, Inbred C57BL, Oxygen, Programmed Cell Death 1 Receptor, Stress, Physiological, Treatment Outcome, Tumor Microenvironment
Abstract

<p>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.</p>

DOI10.1016/j.ccell.2017.08.004
Alternate JournalCancer Cell
PubMed ID28898698
PubMed Central IDPMC5751418
Grant ListP50 CA101942 / CA / NCI NIH HHS / United States
S10 OD017998 / OD / NIH HHS / United States
P30 CA010815 / CA / NCI NIH HHS / United States
P01 CA114046 / CA / NCI NIH HHS / United States
P50 CA174523 / CA / NCI NIH HHS / United States