Immunological and pathological characteristics of brain parenchymal and leptomeningeal metastases from non-small cell lung cancer.

IF 12.5 1区 生物学 Q1 CELL BIOLOGY
Cheng Zhou, Shenbing Shan, Lei Wen, Da Liu, Changguo Shan, Xin Jin, Zhaoming Zhou, Hainan Li, Juan Li, Luyue Wang, Junguo Bu, Bin Li, Weishan Huang, Junhao Hu, Hongbo Guo, Wu Wei
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Abstract

Brain parenchymal metastases (BM) and leptomeningeal metastases (LM) represent distinct subtypes of central nervous system metastases (CNSm) from lung cancer, posing significant clinical challenges. The local immune landscape of LM remains elusive. Herein, we utilized single-cell RNA sequencing to build a cell atlas of LM, and systematically examine the immune profiling and cell heterogeneity between BM and LM. Our analysis reveals that BM has more CXCL9+ macrophages, CXCL13+CD4+ T cells and B cells than LM, exhibiting the presence of tertiary lymphoid (TLS) structures, which is associated with a favorable response to tyrosine kinase inhibitors (TKI). Conversely, a remarkably immunosuppressive tumor microenvironment (TME) is detected in LM, characterized by lymphocyte depletion and a concurrent enrichment of SPP1+ macrophages, compared to BM. Furthermore, we identified significant blood-brain barrier (BBB) cell discrepancies between BM and LM, and substantial phenotypic reprogramming of BBB cells in CNSm. This reprogramming encompassed alterations in transporter gene expression, extracellular matrix production and dysregulated cell-cell interactions, potentially contributing to the metastatic process. In summary, this study highlights the divergent cellular and molecular landscapes of BM vs LM, offering critical insights into potential therapeutic targets and informing the development of improved treatment strategies for non-small cell lung cancer patients with CSNm.

非小细胞肺癌脑实质和脑轻脑膜转移的免疫学和病理学特征。
脑实质转移(BM)和脑轻脑膜转移(LM)代表了肺癌中枢神经系统转移(CNSm)的不同亚型,提出了重大的临床挑战。LM的局部免疫景观仍然难以捉摸。在此,我们利用单细胞RNA测序建立了LM的细胞图谱,并系统地检查了BM和LM之间的免疫谱和细胞异质性。我们的分析显示,与LM相比,BM有更多的CXCL9+巨噬细胞、CXCL13+CD4+ T细胞和B细胞,显示出三级淋巴细胞(TLS)结构的存在,这与酪氨酸激酶抑制剂(TKI)的良好反应有关。相反,与BM相比,LM中检测到明显的免疫抑制肿瘤微环境(TME),其特征是淋巴细胞减少,同时SPP1+巨噬细胞富集。此外,我们还发现了脑屏障(BBB)细胞在脑脊液和脑脊液中的显著差异,以及脑脊液中BBB细胞的表型重编程。这种重编程包括转运蛋白基因表达、细胞外基质产生和细胞间相互作用失调的改变,可能导致转移过程。总之,本研究突出了BM与LM不同的细胞和分子景观,为潜在的治疗靶点提供了重要的见解,并为非小细胞肺癌合并CSNm患者的改进治疗策略的发展提供了信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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