布莱根妇女医院Francisco J. Quintana小组在研究中取得进展。他们报道了胶质母细胞瘤诱导的星形胶质细胞抑制肿瘤特异性T细胞免疫。相关论文发表在2025年5月21日出版的《自然》杂志上。

在这里，课题组对临床胶质母细胞瘤样本和临床前模型样本、多路免疫荧光、体内基于CRISPR的细胞特异性遗传扰动以及体外motheme和人体实验系统进行了单细胞和大量RNA测序，以解决这一知识空白。课题组研究人员发现了一个星形胶质细胞亚群，通过死亡受体配体TRAIL诱导T细胞凋亡来限制肿瘤免疫。

此外，该课题组研究人员发现肿瘤细胞产生的IL-11是星形胶质细胞中STAT3依赖性TRAIL表达的驱动因素。胶质母细胞瘤患者通过STAT3和TRAIL表达的星形胶质细胞信号与更短的复发时间和总体生存率降低相关。星形胶质细胞中IL-11受体或TRAIL的基因失活延长了胶质母细胞瘤模型的生存期，并增强了T细胞和巨噬细胞反应。最后，通过在肿瘤微环境中表达TRAIL阻断单链抗体的溶瘤性HSV-1病毒进行治疗，延长了胶质母细胞瘤临床前模型的生存期，增强了肿瘤特异性免疫。总之，研究小组证实IL-11–STAT3驱动的星形胶质细胞通过诱导TRAIL依赖性T细胞凋亡和工程化治疗病毒主题可以靶向星形胶质细胞驱动的肿瘤免疫逃避机制。

据悉，胶质母细胞瘤是最常见和侵袭性的原发性脑癌，对治疗反应最小。胶质母细胞瘤的免疫抑制肿瘤微环境有助于有限的治疗反应。星形胶质细胞在中枢神经系统中丰富，具有重要的免疫调节作用。然而，它们在胶质母细胞瘤免疫反应中的作用知之甚少。

附：英文原文

Title: Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity

Author: Faust Akl, Camilo, Andersen, Brian M., Li, Zhaorong, Giovannoni, Federico, Diebold, Martin, Sanmarco, Liliana M., Kilian, Michael, Fehrenbacher, Luca, Pernin, Florian, Rone, Joseph M., Lee, Hong-Gyun, Piester, Gavin, Kenison, Jessica E., Lee, Joon-Hyuk, Illouz, Tomer, Polonio, Carolina M., Srun, Lna, Martinez, Jazmin, Chung, Elizabeth N., Schle, Anton, Plasencia, Agustin, Li, Lucinda, Ferrara, Kylynne, Lewandrowski, Mercedes, Strathdee, Craig A., Lerner, Lorena, Quva, Christophe, Clark, Iain C., Deneen, Benjamin, Lieberman, Judy, Sherr, David H., Antel, Jack P., Wheeler, Michael A., Ligon, Keith L., Chiocca, E. Antonio, Prinz, Marco, Reardon, David A., Quintana, Francisco J.

Issue&Volume: 2025-05-21

Abstract: Glioblastoma is the most common and aggressive primary brain cancer and shows minimal response to therapies. The immunosuppressive tumour microenvironment in glioblastoma contributes to the limited therapeutic response. Astrocytes are abundant in the central nervous system and have important immunoregulatory roles. However, little is known about their role in the immune response to glioblastoma1. Here we used single-cell and bulk RNA sequencing of clinical glioblastoma samples and samples from preclinical models, multiplexed immunofluorescence, in vivo CRISPR-based cell-specific genetic perturbations and in vitro mouse and human experimental systems to address this gap in knowledge. We identified an astrocyte subset that limits tumour immunity by inducing Tcell apoptosis through the death receptor ligand TRAIL. Moreover, we identified that IL-11 produced by tumour cells is a driver of STAT3-dependent TRAIL expression in astrocytes. Astrocyte signalling through STAT3 and TRAIL expression were associated with a shorter time to recurrence and overall decreased survival in patients with glioblastoma. Genetic inactivation of the IL-11 receptor or TRAIL in astrocytes extended survival in mouse models of glioblastoma and enhanced Tcell and macrophage responses. Finally, treatment with an oncolytic HSV-1 virus engineered to express a TRAIL-blocking single-chain antibody in the tumour microenvironment extended survival and enhanced tumour-specific immunity in preclinical models of glioblastoma. In summary, we establish that IL-11–STAT3-driven astrocytes suppress glioblastoma-specific protective immunity by inducing TRAIL-dependent Tcell apoptosis, and engineered therapeutic viruses can be used to target this mechanism of astrocyte-driven tumour immunoevasion.

DOI: 10.1038/s41586-025-08997-x

Source: https://www.nature.com/articles/s41586-025-08997-x