Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity
Ringel, Alison E.; Drijvers, Jefte M.; Baker, Gregory J.; Catozzi, Alessia; Garcia-Canaveras, Juan C.; Gassaway, Brandon M.; Miller, Brian C.; Juneja, Vikram R.; Nguyen, Thao H.; Joshi, Shakchhi; Yao, Cong-Hui; Yoon, Haejin; Sage, Peter T.; LaFleur, Martin
CELL
2020
VL / 183 - BP / 1848 - EP / +
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.
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