Cell
Volume 183, Issue 7, 23 December 2020, Pages 1848-1866.e26
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Article
Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity

https://doi.org/10.1016/j.cell.2020.11.009Get rights and content
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Highlights

  • Defined a metabolic single-cell atlas of the tumor immune landscape with obesity

  • Obesity induces a metabolic tug of war between tumor and T cells for lipids

  • Tumor cells induce fat metabolism and change their microenvironment during obesity

  • Blocking metabolic adaptations to obesity in cancers restores anti-tumor immunity

Summary

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

tumor microenvironment
anti-tumor immunity
CD8+ T cells
obesity
colorectal cancer
metabolism
fat oxidation

Cited by (0)

8

Present address: Third Rock Ventures, Boston, MA 02116, USA

9

Present address: Cancer Biomarker Centre, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK

10

Present address: BioNTech SE, Cambridge, MA 02139, USA

11

Present address: Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

12

Present address: Michigan State University, East Lansing, MI 48824, USA

13

These authors contributed equally

14

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