美国布莱根妇女医院Francisco J. Quintana小组取得一项新突破。他们提出了条形码病毒追踪识别免疫抑制星形胶质细胞-胶质瘤相互作用。2025年6月25日出版的《自然》发表了这项成果。

在这里，该课题组描述了一种病毒条形码相互作用追踪方法，以单细胞分辨率分析GBM临床样本和临床前模型中的TME细胞-细胞通信。研究人员将其与单细胞和大量RNA测序分析、人类器官型GBM培养、体内细胞特异性CRISPR–Cas9驱动的遗传干扰以及人类和小鼠实验系统相结合，以鉴定限制肿瘤特异性免疫的膜联蛋白A1 -甲酰基肽受体1（ANXA1-FPR1）双向星形胶质细胞- GBM通讯途径。FPR1抑制肿瘤细胞免疫原性坏死，ANXA1抑制星形胶质细胞NF-κB和炎性体活化。

星形胶质细胞中的ANXA1表达和癌细胞中的FPR1表达与GBM患者的不良预后相关。星形胶质细胞-胶质瘤ANXA1-FPR1信号的失活增强了树突状细胞、T细胞和巨噬细胞的反应，增加了肿瘤特异性CD8⁺ T细胞的浸润，并限制了T细胞的衰竭。总之，该课题组已经开发了一种方法来分析临床样品和临床前模型中单细胞分辨率的TME细胞-细胞相互作用，并通过ANXA1-FPR1确定星形胶质细胞-GBM双向通信，作为免疫逃避和肿瘤进展的驱动因素。

研究人员表示，胶质母细胞瘤（GBM）是最致命的原发性脑恶性肿瘤。GBM肿瘤微环境（TME）中的免疫抑制是免疫靶向治疗的重要障碍，但他们对GBM TME中免疫调节机制的了解有限。

附：英文原文

Title: Barcoded viral tracing identifies immunosuppressive astrocyte–glioma interactions

Author: Andersen, Brian M., Faust Akl, Camilo, Wheeler, Michael A., Li, Zhaorong, Diebold, Martin, Kilian, Michael, Rone, Joseph M., Misra, Aditya, Kenison, Jessica E., Lee, Joon-Hyuk, Lee, Hong-Gyun, Polonio, Carolina M., Merrell, David, Weiss, Jakob H., Godinez, Lillie, Piester, Gavin, Illouz, Tomer, Ye, Jessica J., Ghia, Arianna, Martinez, Jazmin, Chung, Elizabeth N., Srun, Lena, Farrenkopf, Daniel, Flausino, Lucas E., Schle, Anton M., Sanmarco, Liliana M., Giovannoni, Federico, Fehrenbacher, Luca, Charabati, Marc, Gutirrez-Vzquez, Cristina, Cusick, Margaret M., Prabhakar, Prem S., Bossi, Connor C., Lapinskas, Emily, Nowarski, Roni, Getz, Gad, Ligon, Keith L., Prinz, Marco, Chiocca, E. Antonio, Reardon, David A., Quintana, Francisco J.

Issue&Volume: 2025-06-25

Abstract: Glioblastoma (GBM) is the most lethal primary brain malignancy1. Immunosuppression in the GBM tumour microenvironment (TME) is an important barrier to immune-targeted therapies, but our understanding of the mechanisms of immune regulation in the GBM TME is limited2. Here we describe a viral barcode interaction-tracing approach3 to analyse TME cell–cell communication in GBM clinical samples and preclinical models at single-cell resolution. We combine it with single-cell and bulk RNA-sequencing analyses, human organotypic GBM cultures, in vivo cell-specific CRISPR–Cas9-driven genetic perturbations as well as human and mouse experimental systems to identify an annexin A1–formyl peptide receptor 1 (ANXA1–FPR1) bidirectional astrocyte–GBM communication pathway that limits tumour-specific immunity. FPR1 inhibits immunogenic necroptosis in tumour cells, and ANXA1 suppresses NF-κB and inflammasome activation in astrocytes. ANXA1 expression in astrocytes and FPR1 expression in cancer cells are associated with poor outcomes in individuals with GBM. The inactivation of astrocyte–glioma ANXA1–FPR1 signalling enhanced dendritic cell, T cell and macrophage responses, increasing infiltration by tumour-specific CD8+ T cells and limiting T cell exhaustion. In summary, we have developed a method to analyse TME cell–cell interactions at single-cell resolution in clinical samples and preclinical models, and used it to identify bidirectional astrocyte–GBM communication through ANXA1–FPR1 as a driver of immune evasion and tumour progression.

DOI: 10.1038/s41586-025-09191-9

Source: https://www.nature.com/articles/s41586-025-09191-9