Brain Tumor Stem Cell Laboratory, Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, USA.
Laboratory of Neural Stem Cells and Functional Neurogenetics, Departments of Neuroscience, Neurology, Genetics and Genome Sciences, UConn Health, Farmington, CT, 06030, USA.
J Neurooncol. 2023 Jan;161(1):67-76. doi: 10.1007/s11060-022-04205-2. Epub 2023 Jan 3.
Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults with a median overall survival of only 14.6 months despite aggressive treatment. While immunotherapy has been successful in other cancers, its benefit has been proven elusive in GBM, mainly due to a markedly immunosuppressive tumor microenvironment. SARS-CoV-2 has been associated with the development of a pronounced central nervous system (CNS) inflammatory response when infecting different cells including astrocytes, endothelial cells, and microglia. While SARS-CoV2 entry factors have been described in different tissues, their presence and implication on GBM aggressiveness or microenvironment has not been studied on appropriate preclinical models.
We evaluated the presence of crucial SARS-CoV-2 entry factors: ACE2, TMPRSS2, and NRP1 in matched surgically-derived GBM tissue, cells lines, and organoids; as well as in human brain derived specimens using immunohistochemistry, confocal pixel line intensity quantification, and transcriptome analysis.
We show that patient derived-GBM tissue and cell cultures express SARS-CoV2 entry factors, being NRP1 the most crucial facilitator of SARS-CoV-2 infection in GBM. Moreover, we demonstrate that, receptor expression remains present in our GBM organoids, making them an adequate model to study the effect of this virus in GBM for the potential development of viral therapies in the future.
Our findings suggest that the SARS-CoV-2 virus entry factors are expressed in primary tissues and organoid models and could be potentially utilized to study the susceptibility of GBM to this virus to target or modulate the tumor microenviroment.
尽管采用了积极的治疗方法，胶质母细胞瘤（GBM）仍是成人中最常见和恶性程度最高的原发性脑肿瘤，中位总生存期仅为 14.6 个月。虽然免疫疗法在其他癌症中取得了成功，但在 GBM 中其疗效却难以捉摸，主要是由于肿瘤微环境明显具有免疫抑制性。SARS-CoV-2 感染包括星形胶质细胞、内皮细胞和小胶质细胞在内的不同细胞时，会引起明显的中枢神经系统（CNS）炎症反应。虽然已经描述了 SARS-CoV2 进入不同组织的因素，但它们在 GBM 侵袭性或微环境中的存在及其意义尚未在适当的临床前模型中进行研究。
我们评估了关键的 SARS-CoV-2 进入因素：在匹配的手术切除的 GBM 组织、细胞系和类器官中，以及在人类大脑来源的标本中，使用免疫组织化学、共聚焦像素线强度定量和转录组分析来评估 ACE2、TMPRSS2 和 NRP1 的存在。
我们表明，患者来源的 GBM 组织和细胞培养物表达 SARS-CoV2 进入因素，NRP1 是 SARS-CoV-2 感染 GBM 的最关键促进剂。此外，我们证明，在我们的 GBM 类器官中，受体表达仍然存在，使它们成为研究该病毒在 GBM 中作用的合适模型，以便将来开发病毒疗法。
我们的研究结果表明，SARS-CoV-2 病毒进入因素在原发性组织和类器官模型中表达，并且可能被用于研究 GBM 对这种病毒的易感性，以靶向或调节肿瘤微环境。
