Advanced Science (Oct 2024)
Lactylated Apolipoprotein C‐II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis
- 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,
- Guangjian Fan
Affiliations
- Jian Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Tongji University 507 Zhengmin Road Shanghai 200433 P. R. China
- Deping Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Tongji University 507 Zhengmin Road Shanghai 200433 P. R. China
- Yupeng Wang
- Department of General Surgery, Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai 200011 P. R. China
- Ming Liu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Tongji University 507 Zhengmin Road Shanghai 200433 P. R. China
- Yuan Zhang
- Department of Gastrointestinal Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201620 P. R. China
- Tingting Feng
- Department of Clinical Pharmacy Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201620 P. R. China
- Chao Xiao
- Department of Gastrointestinal Surgery Shanghai East Hospital, School of Medicine Tongji University Shanghai 200040 P. R. China
- Huan Song
- Department of Clinical Laboratory Medicine Shanghai Pulmonary Hospital Tongji University School of Medicine Shanghai 200433 P. R. China
- Rui Miao
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- Li Xu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Tongji University 507 Zhengmin Road Shanghai 200433 P. R. China
- Hongwei Chen
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- Xiaoying Qiu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- Yi Xu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- Jingxuan Xu
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty Mannheim Heidelberg University 68167 Mannheim Germany
- Zelin Cui
- Department of Laboratory Medicine Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201620 P. R. China
- Wei Wang
- Department of Breast‐thyroid Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201620 P. R. China
- Yanchun Quan
- Central Laboratory Linyi People's Hospital Shandong 273300 P. R. China
- Yifeng Zhu
- Department of Internal Medicine II, Klinikum rechts der Isar Technical University of Munich Ismaninger Str. 22 81675 Munich Germany
- Chen Huang
- Department of Gastrointestinal Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201620 P. R. China
- Song Guo Zheng
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital Shanghai 200080 P. R. China
- Jian‐yuan Zhao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE‐Shanghai Key Laboratory of Children's Environmental Health Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200092 P. R. China
- Ting Zhu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- Lianhui Sun
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- Guangjian Fan
- Precision Research Center for Refractory Diseases, Institute for Clinical Research Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 P. R. China
- DOI
- https://doi.org/10.1002/advs.202406333
- Journal volume & issue
-
Vol. 11,
no. 38
pp. n/a – n/a
Abstract
Abstract 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.
Keywords
