Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC
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.
Authors
- Shouheng Lin (ORCID: https://orcid.org/0000-0002-6248-5926)
- Yang-Si Li (ORCID: https://orcid.org/0009-0008-1372-4418)
- Kai Yin (ORCID: https://orcid.org/0000-0001-8802-766X)
- Fa-Man Xiao
- Lu Zeng
- Oscar Junhong Luo (ORCID: https://orcid.org/0000-0002-1266-3069)
- Zhi Hong Chen (ORCID: https://orcid.org/0000-0001-6048-5917)
- Bin-Chao Wang
- Jiaxin Lin (ORCID: https://orcid.org/0000-0001-8636-294X)
- Hai‐Yan Tu (ORCID: https://orcid.org/0000-0001-7125-9878)
- Yue‐Li Sun (ORCID: https://orcid.org/0000-0002-6109-9978)
- Yi Pan (ORCID: https://orcid.org/0000-0003-4945-5631)
- Xue‐Ning Yang (ORCID: https://orcid.org/0000-0002-8346-2117)
- Xu‐Chao Zhang (ORCID: https://orcid.org/0000-0002-4138-8115)
- Yangqiu Li (ORCID: https://orcid.org/0000-0002-0974-4036)
- Mei-Mei Zheng (ORCID: https://orcid.org/0000-0002-3493-7139)
- Qing Zhou (ORCID: https://orcid.org/0000-0002-0478-176X)
- Zhen Wang (ORCID: https://orcid.org/0000-0002-4456-8752)
- Si‐Yang Maggie Liu (ORCID: https://orcid.org/0000-0002-3837-0758)
- Yi-Long Lung Cancer Wu (ORCID: https://orcid.org/0000-0002-3611-0258)
- Hao Sun (ORCID: https://orcid.org/0000-0002-4329-3910)
- Jin‐Ji Yang (ORCID: https://orcid.org/0000-0002-8498-0119)
- Xiaoyan Bai (ORCID: https://orcid.org/0000-0003-0697-4378)
- Ben‐Yuan Jiang
- Wen-Pu Lai
- Liang Li
- Erjing Ke
- Wei‐Bang Guo
- Wen-Zhao Zhong
- Huajun Chen (ORCID: https://orcid.org/0000-0002-0998-3387)
Institutions
- Jinan University (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- State Key Laboratory of Respiratory Disease (CN)
- First Affiliated Hospital of Jinan University (CN)
- Southern Medical University (CN)
- University of Hong Kong (HK)
- South China University of Technology (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114613
- Citations
- 19
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 7.96