Blomberg Evelina, Silginer Manuela, Roth Patrick, Weller Michael
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Zürich.
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Transl Oncol. 2023 Feb;28:101607. doi: 10.1016/j.tranon.2022.101607. Epub 2022 Dec 24.
Despite multimodal treatment approaches including surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma remains in the range of one year and thus poor. Type I interferons (IFN) are involved in immune responses to viral infection and exhibit anti-tumor activity in certain cancers. Here we explored the biological relevance of constitutive type I IFN signaling in murine glioma models in vitro and in vivo. CT-2A, GL-261, SMA-497, SMA-540 and SMA-560 murine glioma cells expressed IFN type I receptors IFNAR1 and IFNAR2 and were responsive to exogenous IFN stimulation. CRISPR/Cas9-mediated deletion of IFNAR1 decreased the baseline expression of type I IFN response genes in GL-261 cells, but neither in CT-2A nor in SMA-560 cells. IFNAR1 deletion slowed growth in GL-261 and SMA-560, but not in CT-2A cells. However, only the growth of IFNAR1-depleted GL-261 tumors and not that of SMA-560 tumors was delayed in vivo upon orthotopic tumor cell implantation into syngeneic mice. This survival gain was no longer detected when the IFNAR1-depleted GL-261 cells were inoculated into IFNAR1-deficient mice. Altogether these data suggest that constitutive type I IFN signaling in gliomas may be pro-tumorigenic, but only in a microenvironment that is proficient for type I IFN signaling in the host.
尽管采用了包括手术、放疗和化疗在内的多模式治疗方法，但胶质母细胞瘤患者的中位生存期仍在一年左右，因此预后较差。I型干扰素（IFN）参与对病毒感染的免疫反应，并在某些癌症中表现出抗肿瘤活性。在这里，我们在体外和体内的小鼠胶质瘤模型中探讨了组成型I型IFN信号传导的生物学相关性。CT-2A、GL-261、SMA-497、SMA-540和SMA-560小鼠胶质瘤细胞表达I型干扰素受体IFNAR1和IFNAR2，并对外源性IFN刺激有反应。CRISPR/Cas9介导的IFNAR1缺失降低了GL-261细胞中I型IFN反应基因的基线表达，但在CT-2A细胞和SMA-560细胞中均未降低。IFNAR1缺失减缓了GL-261和SMA-560细胞的生长，但对CT-2A细胞没有影响。然而，在将原位肿瘤细胞植入同基因小鼠体内后，只有IFNAR1缺失的GL-261肿瘤的生长延迟，而SMA-560肿瘤的生长没有延迟。当将IFNAR1缺失的GL-261细胞接种到IFNAR1缺陷小鼠中时，不再检测到这种生存获益。总之，这些数据表明，胶质瘤中的组成型I型IFN信号传导可能具有促肿瘤作用，但仅在宿主中I型IFN信号传导功能正常的微环境中如此。
