Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Author Alison Ringel, Jefte Drijvers, Gregory Baker, Alessia Catozzi, Juan García-Cañaveras, Brandon Gassaway, Brian Miller, Vikram Juneja, Thao Nguyen, Shakchhi Joshi, Cong-Hui Yao, Haejin Yoon, Peter Sage, Martin LaFleur, Justin Trombley, Connor Jacobson, Zoltan Maliga, Steven Gygi, Peter Sorger, Joshua Rabinowitz, Arlene Sharpe, Marcia Haigis Publication Year 2020 Type Journal Article Abstract 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. Keywords Animals, Humans, Cell Proliferation, Fatty Acids, Kinetics, Mice, Inbred C57BL, HEK293 Cells, Mice, Knockout, Proteomics, Cell Line, Tumor, Principal Component Analysis, Oxidation-Reduction, Tumor Microenvironment, Neoplasms, Obesity, CD8-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Diet, High-Fat, Immunity, Adiposity, Hypoxia-Inducible Factor-Proline Dioxygenases, Procollagen-Proline Dioxygenase Journal Cell Volume 183 Issue 7 Pages 1848-1866.e26 Date Published 2020 Dec 23 ISSN Number 1097-4172 DOI 10.1016/j.cell.2020.11.009 Alternate Journal Cell PMCID PMC8064125 PMID 33301708 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML