Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells

Sicheng Fu, Kaixin He, Chenxi Tian, Hua Sun, Chenwen Zhu, Shiyu Bai, Jiwei Liu, Qielan Wu, Di Xie, Ting Yue, Zhuxia Shen, Qingqing Dai, Xiaojun Yu, Shu Zhu, Gang Liu, Rongbin Zhou, Shengzhong Duan, Zhigang Tian, Tao Xu, Hua Wang () and Li Bai ()
Additional contact information
Sicheng Fu: University of Science and Technology of China
Kaixin He: University of Science and Technology of China
Chenxi Tian: University of Science and Technology of China
Hua Sun: The First Affiliated Hospital of Anhui Medical University, Anhui Medical University
Chenwen Zhu: The First Affiliated Hospital of Anhui Medical University, Anhui Medical University
Shiyu Bai: University of Science and Technology of China
Jiwei Liu: University of Science and Technology of China
Qielan Wu: University of Science and Technology of China
Di Xie: University of Science and Technology of China
Ting Yue: University of Science and Technology of China
Zhuxia Shen: Fudan University
Qingqing Dai: The First Affiliated Hospital of Anhui Medical University
Xiaojun Yu: The First Affiliated Hospital of Anhui Medical University
Shu Zhu: University of Science and Technology of China
Gang Liu: University of Science and Technology of China
Rongbin Zhou: University of Science and Technology of China
Shengzhong Duan: Shanghai Jiao Tong University School of Medicine
Zhigang Tian: University of Science and Technology of China
Tao Xu: Chinese Academy of Sciences
Hua Wang: The First Affiliated Hospital of Anhui Medical University, Anhui Medical University
Li Bai: University of Science and Technology of China

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

Date: 2020
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DOI: 10.1038/s41467-020-14332-x

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