Cell reports · 2024
Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Li Yang-Si, Lai Wen-Pu, Yin Kai, Zheng Mei-Mei, Tu Hai-Yan, Guo Wei-Bang, Li Liang, Lin Shou-Heng, Wang Zhen, Zeng Lu, Jiang Ben-Yuan, Chen Zhi-Hong, Zhou Qing, Zhang Xu-Chao, Yang Jin-Ji, Zhong Wen-Zhao, Yang Xue-Ning, Wang Bin-Chao, Pan Yi, Chen Hua-Jun, Xiao Fa-Man, Sun Hao, Sun Yue-Li, Bai Xiao-Yan, Ke E-E, Lin Jia-Xin, Liu Si-Yang Maggie, Li Yangqiu, Luo Oscar Junhong, Wu Yi-Long
Аннотация
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.