Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.

TitleObesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.
Publication TypeJournal Article
Year of Publication2020
AuthorsRingel, AE, Drijvers, JM, Baker, GJ, Catozzi, A, García-Cañaveras, JC, Gassaway, BM, Miller, BC, Juneja, VR, Nguyen, TH, Joshi, S, Yao, C-H, Yoon, H, Sage, PT, LaFleur, MW, Trombley, JD, Jacobson, CA, Maliga, Z, Gygi, SP, Sorger, PK, Rabinowitz, JD, Sharpe, AH, Haigis, MC
JournalCell
Volume183
Issue7
Pagination1848-1866.e26
Date Published2020 12 23
ISSN1097-4172
KeywordsAdiposity, Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cell Proliferation, Diet, High-Fat, Fatty Acids, HEK293 Cells, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Immunity, Kinetics, Lymphocytes, Tumor-Infiltrating, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Obesity, Oxidation-Reduction, Principal Component Analysis, Procollagen-Proline Dioxygenase, Proteomics, Tumor Microenvironment
Abstract

<p>Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8 T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8 T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8 T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8 T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8 T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.</p>

DOI10.1016/j.cell.2020.11.009
Alternate JournalCell
PubMed ID33301708
PubMed Central IDPMC8064125
Grant ListU54 CA225088 / CA / NCI NIH HHS / United States
P01 AI056299 / AI / NIAID NIH HHS / United States
R01 DK103295 / DK / NIDDK NIH HHS / United States
F31 CA224601 / CA / NCI NIH HHS / United States
R01 CA213062 / CA / NCI NIH HHS / United States
T32 CA207021 / CA / NCI NIH HHS / United States