The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot, Israel.
Cell Rep. 2021 Aug 3;36(5):109480. doi: 10.1016/j.celrep.2021.109480.
Recent multi-omics studies show different immune tumor microenvironment (TME) compositions in glioblastoma (GBM). However, temporal comprehensive knowledge of the TME from initiation of the disease remains sparse. We use Cre recombinase (Cre)-inducible lentiviral murine GBM models to compare the cellular evolution of the immune TME in tumors initiated from different oncogenic drivers. We show that neutrophils infiltrate early during tumor progression primarily in the mesenchymal GBM model. Depleting neutrophils in vivo at the onset of disease accelerates tumor growth and reduces the median overall survival time of mice. We show that, as a tumor progresses, bone marrow-derived neutrophils are skewed toward a phenotype associated with pro-tumorigenic processes. Our findings suggest that GBM can remotely regulate systemic myeloid differentiation in the bone marrow to generate neutrophils pre-committed to a tumor-supportive phenotype. This work reveals plasticity in the systemic immune host microenvironment, suggesting an additional point of intervention in GBM treatment.
最近的多组学研究表明，胶质母细胞瘤（GBM）中的免疫肿瘤微环境（TME）组成存在差异。然而，从疾病开始时对 TME 的全面时间认知仍然很少。我们使用 Cre 重组酶（Cre）诱导的慢病毒小鼠 GBM 模型，比较了由不同致癌驱动因素引发的肿瘤中免疫 TME 的细胞进化。我们发现，中性粒细胞在肿瘤进展的早期主要在间充质 GBM 模型中浸润。在疾病开始时在体内耗尽中性粒细胞会加速肿瘤生长并降低小鼠的中位总生存期。我们发现，随着肿瘤的进展，骨髓来源的中性粒细胞向与促肿瘤过程相关的表型倾斜。我们的研究结果表明，GBM 可以远程调节骨髓中的系统髓样分化，从而产生预先承诺为肿瘤支持表型的中性粒细胞。这项工作揭示了系统免疫宿主微环境的可塑性，为 GBM 治疗提供了另一个干预点。
