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Lactylated apolipoprotein C-II induces immunotherapy resistance by promoting extracellular lipolysis

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links...

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Main Authors: Chen, Jian (Author) , Zhao, Deping (Author) , Wang, Yupeng (Author) , Liu, Ming (Author) , Zhang, Yuan (Author) , Feng, Tingting (Author) , Xiao, Chao (Author) , Song, Huan (Author) , Miao, Rui (Author) , Xu, Li (Author) , Chen, Hongwei (Author) , Qiu, Xiaoying (Author) , Xu, Yi (Author) , Xu, Jingxuan (Author) , Cui, Zelin (Author) , Wang, Wei (Author) , Quan, Yanchun (Author) , Zhu, Yifeng (Author) , Huang, Chen (Author) , Zheng, Song Guo (Author) , Zhao, Jian-yuan (Author) , Zhu, Ting (Author) , Sun, Lianhui (Author) , Fan, Guangjian (Author)
Format: Article (Journal)
Language:English
Published: October 16, 2024
In: Advanced science
Year: 2024, Volume: 11, Issue: 38, Pages: 1-18
ISSN:2198-3844
DOI:10.1002/advs.202406333
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/advs.202406333
Verlag, kostenfrei, Volltext: http://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202406333
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Author Notes:Jian Chen, Deping Zhao, Yupeng Wang, Ming Liu, Yuan Zhang, Tingting Feng, Chao Xiao, Huan Song, Rui Miao, Li Xu, Hongwei Chen, Xiaoying Qiu, Yi Xu, Jingxuan Xu, Zelin Cui, Wei Wang, Yanchun Quan, Yifeng Zhu, Chen Huang, Song Guo Zheng, Jian-yuan Zhao, Ting Zhu, Lianhui Sun, and Guangjian Fan
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Summary:Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.
Item Description:Erstmals veröffentlicht: 09. Juli 2024
Gesehen am 18.11.2024
Physical Description:Online Resource
ISSN:2198-3844
DOI:10.1002/advs.202406333

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