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
  • 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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