2. Academic Validation
  3. Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis

Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis

  • Adv Sci (Weinh). 2024 Jul 9:e2406333. doi: 10.1002/advs.202406333.
Jian Chen 1 2,  Deping Zhao 2,  Yupeng Wang 3,  Ming Liu 2,  Yuan Zhang 4,  Tingting Feng 5,  Chao Xiao 6,  Huan Song 7,  Rui Miao 1,  Li Xu 2,  Hongwei Chen 1,  Xiaoying Qiu 1,  Yi Xu 1,  Jingxuan Xu 8,  Zelin Cui 9,  Wei Wang 10,  Yanchun Quan 11,  Yifeng Zhu 12,  Chen Huang 4,  Song Guo Zheng 1 4,  Jian-Yuan Zhao 13,  Ting Zhu 1,  Lianhui Sun 1 14,  Guangjian Fan 1
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, 507 Zhengmin Road, Shanghai, 200433, P. R. China.
  • 3 Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China.
  • 4 Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, P. R. China.
  • 5 Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, P. R. China.
  • 6 Department of Gastrointestinal Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200040, P. R. China.
  • 7 Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P. R. China.
  • 8 Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
  • 9 Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, P. R. China.
  • 10 Department of Breast-thyroid Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, P. R. China.
  • 11 Central Laboratory, Linyi People's Hospital, Shandong, 273300, P. R. China.
  • 12 Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.
  • 13 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.
  • 14 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.
PMID: 38981044 DOI: 10.1002/advs.202406333
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

APOC2; lipolysis; lysine‐lactylation; non‐small cell lung cancer.

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