Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk

Alexander Piening, Emily Ebert, Carter Gottlieb, Niloufar Khojandi, Lindsey M. Kuehm, Stella G. Hoft, Kelly D. Pyles, Kyle S. McCommis, Richard J. DiPaolo, Stephen T. Ferris, Elise Alspach and Ryan M. Teague ()
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Alexander Piening: Saint Louis University School of Medicine
Emily Ebert: Saint Louis University School of Medicine
Carter Gottlieb: Saint Louis University School of Medicine
Niloufar Khojandi: Saint Louis University School of Medicine
Lindsey M. Kuehm: Saint Louis University School of Medicine
Stella G. Hoft: Saint Louis University School of Medicine
Kelly D. Pyles: Saint Louis University School of Medicine
Kyle S. McCommis: Saint Louis University School of Medicine
Richard J. DiPaolo: Saint Louis University School of Medicine
Stephen T. Ferris: Saint Louis University School of Medicine
Elise Alspach: Saint Louis University School of Medicine
Ryan M. Teague: Saint Louis University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Obesity is a well-established risk factor for human cancer, yet the underlying mechanisms remain elusive. Immune dysfunction is commonly associated with obesity but whether compromised immune surveillance contributes to cancer susceptibility in individuals with obesity is unclear. Here we use a mouse model of diet-induced obesity to investigate tumor-infiltrating CD8 + T cell responses in lean, obese, and previously obese hosts that lost weight through either dietary restriction or treatment with semaglutide. While both strategies reduce body mass, only dietary intervention restores T cell function and improves responses to immunotherapy. In mice exposed to a chemical carcinogen, obesity-related immune dysfunction leads to higher incidence of sarcoma development. However, impaired immunoediting in the obese environment enhances tumor immunogenicity, making the malignancies highly sensitive to immunotherapy. These findings offer insight into the complex interplay between obesity, immunity and cancer, and provide explanation for the obesity paradox observed in clinical immunotherapy settings.

Date: 2024
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DOI: 10.1038/s41467-024-47359-5

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