Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity

Hao Fan, Siyuan Xia, Junhong Xiang, Yuancheng Li, Matthew O. Ross, Seon Ah Lim, Fan Yang, Jiayi Tu, Lishi Xie, Urszula Dougherty, Freya Q. Zhang, Zhong Zheng, Rukang Zhang, Rong Wu, Lei Dong, Rui Su, Xiufen Chen, Thomas Althaus, Peter A. Riedell, Patrick B. Jonker, Alexander Muir, Gregory B. Lesinski, Sarwish Rafiq, Madhav V. Dhodapkar, Wendy Stock, Olatoyosi Odenike, Anand A. Patel, Joseph Opferman, Takemasa Tsuji, Junko Matsuzaki, Hardik Shah, Brandon Faubert, Shannon E. Elf, Brian Layden, B. Marc Bissonnette, Yu-Ying He, Justin Kline, Hui Mao, Kunle Odunsi, Xue Gao, Hongbo Chi (), Chuan He () and Jing Chen ()
Additional contact information
Hao Fan: Emory University
Siyuan Xia: Emory University
Junhong Xiang: The University of Chicago
Yuancheng Li: Emory University
Matthew O. Ross: The University of Chicago
Seon Ah Lim: St Jude Children’s Research Hospital
Fan Yang: The University of Chicago
Jiayi Tu: The University of Chicago
Lishi Xie: The University of Chicago
Urszula Dougherty: The University of Chicago
Freya Q. Zhang: The University of Chicago
Zhong Zheng: The University of Chicago
Rukang Zhang: Emory University
Rong Wu: Emory University
Lei Dong: Beckman Research Institute of City of Hope
Rui Su: Beckman Research Institute of City of Hope
Xiufen Chen: The University of Chicago
Thomas Althaus: The University of Chicago
Peter A. Riedell: The University of Chicago
Patrick B. Jonker: The University of Chicago
Alexander Muir: The University of Chicago
Gregory B. Lesinski: Emory University
Sarwish Rafiq: Emory University
Madhav V. Dhodapkar: Emory University
Wendy Stock: The University of Chicago
Olatoyosi Odenike: The University of Chicago
Anand A. Patel: The University of Chicago
Joseph Opferman: St Jude Children’s Research Hospital
Takemasa Tsuji: The University of Chicago
Junko Matsuzaki: The University of Chicago
Hardik Shah: The University of Chicago
Brandon Faubert: The University of Chicago
Shannon E. Elf: The University of Chicago
Brian Layden: University of Illinois Chicago
B. Marc Bissonnette: The University of Chicago
Yu-Ying He: The University of Chicago
Justin Kline: The University of Chicago
Hui Mao: Emory University
Kunle Odunsi: The University of Chicago
Xue Gao: Emory University
Hongbo Chi: St Jude Children’s Research Hospital
Chuan He: The University of Chicago
Jing Chen: Emory University

Nature, 2023, vol. 623, issue 7989, 1034-1043

Abstract: Abstract Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6–8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP–PKA–CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Date: 2023
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DOI: 10.1038/s41586-023-06749-3

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