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

Huang, Tu-Xiong1,2; Huang, Hui-Si1,2; Dong, Shao-Wei3,4; Chen, Jia-Yan1,2; Zhang, Bin3; Li, Hua-Hui5; Zhang, Tian-Tian1,2; Xie, Qiang1,2; Long, Qiao-Yun3; Yang, Yang1,2; Huang, Lin-Yuan1,2; Zhao, Pan3; Bi, Jiong6; Lu, Xi-Feng7; Pan, Fan5; Zou, Chang3,8; Fu, Li1,2

2024-07-06

10.1038/s41467-024-50077-7

NATURE COMMUNICATIONS   影响因子和分区

2041-1723

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-beta 1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-beta 1 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.

SCI

英语

通讯

National Natural Science Foundation of China["82173003","32370968","82170881","81870605","82173016"] ; National Key R&D Program of China[2017YFA0503900] ; Science and Technology Program of Guangdong Province["2019B030301009","2021A1515010707"] ; Guangdong Basic and Applied Basic Research Foundation[2024A1515010539] ; Science and Technology Foundation of Shenzhen[JCYJ20200109113810154]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001265279400020

NATURE PORTFOLIO

Web of Science

1.Shenzhen Univ, Med Sch, Dept Pharmacol, Guangdong Prov Key Lab Reg Immun & Dis, Shenzhen 518060, Guangdong, Peoples R China
2.Univ Med Sch, Int Canc Ctr, Shenzhen 518060, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Dept Clin Med, Res Ctr,Affiliated Hosp 1, Shenzhen 518000, Guangdong, Peoples R China
4.Shenzhen Childrens Hosp, Dept Hematol & Oncol, Shenzhen 518038, Guangdong, Peoples R China
5.Chinese Acad Sci, Shenzhen Inst Adv Technol SIAT, Shenzhen 518055, Guangdong, Peoples R China
6.Sun Yat sen Univ, Affiliated Hosp 1, Guangzhou 510080, Guangdong, Peoples R China
7.Shantou Univ, Affiliated Hosp 1, Med Coll, Clin Res Ctr, Shantou 515041, Guangdong, Peoples R China
8.Chinese Univ Hong Kong, Sch Life & Hlth Sci, Shenzhen 518000, Guangdong, Peoples R China

Huang, Tu-Xiong,Huang, Hui-Si,Dong, Shao-Wei,et al. ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8⁺ T cells[J]. NATURE COMMUNICATIONS,2024,15(1).

Huang, Tu-Xiong.,Huang, Hui-Si.,Dong, Shao-Wei.,Chen, Jia-Yan.,Zhang, Bin.,...&Fu, Li.(2024).ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8⁺ T cells.NATURE COMMUNICATIONS,15(1).

Huang, Tu-Xiong,et al."ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8⁺ T cells".NATURE COMMUNICATIONS 15.1(2024).