ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells

Tu-Xiong Huang, Hui-Si Huang, Shao-Wei Dong, Jia-Yan Chen, Bin Zhang, Hua-Hui Li, Tian-Tian Zhang, Qiang Xie, Qiao-Yun Long, Yang Yang, Lin-Yuan Huang, Pan Zhao, Jiong Bi, Xi-Feng Lu, Fan Pan, Chang Zou () and Li Fu ()
Additional contact information
Tu-Xiong Huang: Shenzhen University Medical School
Hui-Si Huang: Shenzhen University Medical School
Shao-Wei Dong: The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital)
Jia-Yan Chen: Shenzhen University Medical School
Bin Zhang: The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital)
Hua-Hui Li: Chinese Academy of Sciences (CAS)
Tian-Tian Zhang: Shenzhen University Medical School
Qiang Xie: Shenzhen University Medical School
Qiao-Yun Long: The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital)
Yang Yang: Shenzhen University Medical School
Lin-Yuan Huang: Shenzhen University Medical School
Pan Zhao: The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital)
Jiong Bi: Sun Yat-sen University
Xi-Feng Lu: The First Affiliated Hospital of Shantou University Medical College
Fan Pan: Chinese Academy of Sciences (CAS)
Chang Zou: The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People’s Hospital)
Li Fu: Shenzhen University Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

Date: 2024
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DOI: 10.1038/s41467-024-50077-7

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