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

• Published in: Cell reports (Cambridge) Vol. 43; no. 8; p. 114613
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.08.2024; Elsevier
• Subjects: Acrylamides - pharmacology; Acrylamides - therapeutic use; Aniline Compounds - pharmacology; Aniline Compounds - therapeutic use; Animals; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; CD47 Antigen - genetics; CD47 Antigen - metabolism; Cell Line, Tumor; cerebrospinal fluid; CP: Cancer; CP: Immunology; Drug Resistance, Neoplasm; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Humans; Indoles; leptomeningeal metastases; Lipid Metabolism - drug effects; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; macrophage; Macrophages - drug effects; Macrophages - metabolism; Male; Meningeal Carcinomatosis - drug therapy; Meningeal Carcinomatosis - pathology; Meningeal Carcinomatosis - secondary; Mice; midkine; osimertinib resistance; Phagocytosis - drug effects; Pyrimidines; CP: Immunology; leptomeningeal metastases; CP: Cancer; cerebrospinal fluid; macrophage; midkine; osimertinib resistance
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114613

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. [Display omitted] •Macrophages in CSF of LMs displayed heterogeneity and immunosuppressive properties•Lipid-associated macrophages are linked to osimertinib resistance and LM development•Macrophages are regulated by MDK and may be a prognostic biomarker for LMs•CD47-SIRPA signaling by tumor cells and macrophages facilitates drug resistance Li et al. identify heightened immunosuppressive macrophages within LMs. Lipid-associated macrophages in CSF are associated with osimertinib resistance and LM development. Midkine from malignant epithelial cells potentially regulates LMs and macrophage polarization. CD47-SIRPA interactions between tumor cells and macrophages facilitate immune escape, suggesting potential therapeutic targets.