Title | Enhancing CD8 T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Zhang, 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 |
Journal | Cancer Cell |
Volume | 32 |
Issue | 3 |
Pagination | 377-391.e9 |
Date Published | 2017 Sep 11 |
ISSN | 1878-3686 |
Keywords | Animals, 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, Lymphocyte Activation Gene 3 Protein, 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> |
DOI | 10.1016/j.ccell.2017.08.004 |
Alternate Journal | Cancer Cell |
PubMed ID | 28898698 |
PubMed Central ID | PMC5751418 |
Grant List | P50 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 |