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  3. Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC

Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC

  • Cell Rep. 2024 Aug 27;43(8):114613. doi: 10.1016/j.celrep.2024.114613.
Yang-Si Li 1,  Wen-Pu Lai 2,  Kai Yin 3,  Mei-Mei Zheng 3,  Hai-Yan Tu 3,  Wei-Bang Guo 3,  Liang Li 4,  Shou-Heng Lin 5,  Zhen Wang 3,  Lu Zeng 3,  Ben-Yuan Jiang 3,  Zhi-Hong Chen 3,  Qing Zhou 3,  Xu-Chao Zhang 3,  Jin-Ji Yang 3,  Wen-Zhao Zhong 3,  Xue-Ning Yang 3,  Bin-Chao Wang 3,  Yi Pan 3,  Hua-Jun Chen 3,  Fa-Man Xiao 3,  Hao Sun 3,  Yue-Li Sun 3,  Xiao-Yan Bai 3,  E-E Ke 3,  Jia-Xin Lin 3,  Si-Yang Maggie Liu 6,  Yangqiu Li 6,  Oscar Junhong Luo 7,  Yi-Long Wu 8
Affiliations

Affiliations

  • 1 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080 China; Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; School of Medicine, South China University of Technology, Guangzhou 510006, China; Department of Oncology, Heyuan Hospital of Guangdong Provincial People's Hospital, Heyuan People's Hospital, Heyuan 517000, China.
  • 2 Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China; Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou 510632, China.
  • 3 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080 China; Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 4 Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 5 China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510700, China.
  • 6 Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China.
  • 7 Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou 510632, China. Electronic address: luojh@jnu.edu.cn.
  • 8 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080 China; Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; School of Medicine, South China University of Technology, Guangzhou 510006, China. Electronic address: syylwu@live.cn.
PMID: 39116206 DOI: 10.1016/j.celrep.2024.114613
Abstract

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung Cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA Sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs.

Keywords

CP: Cancer; CP: Immunology; cerebrospinal fluid; leptomeningeal metastases; macrophage; midkine; osimertinib resistance.

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