Center for Stem Cell Therapeutics and Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2020 Aug 6;11(1):3912. doi: 10.1038/s41467-020-17704-5.
Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.
免疫疗法已成为治疗癌症的一种有前途的方法，然而，其在高度恶性脑肿瘤、胶质母细胞瘤（GBM）中的疗效有限。在这里，我们生成了不同的可成像的同源小鼠 GBM 肿瘤模型，并利用 RNA 测序、CyTOF 和相关免疫组织化学来评估这些模型中的免疫谱。我们确定了免疫惰性和免疫活性的同源肿瘤类型，并表明惰性肿瘤具有免疫抑制表型，其中有大量耗竭的 CD8 T 细胞和驻留巨噬细胞；较少的嗜酸性粒细胞和 SiglecF+巨噬细胞。为了模拟 GBM 治疗一线的临床环境，我们表明肿瘤切除通过增加 T 细胞、激活的小胶质细胞和 SiglecF+巨噬细胞以及减少驻留巨噬细胞来增强抗肿瘤反应。对 GBM 患者和小鼠 GBM 肿瘤的切除肿瘤样本进行比较 CyTOF 分析，在测试的一种小鼠 GBM 肿瘤中显示出明显的相似性。这些发现为免疫治疗干预的 GBM 模型的使用提供了明智的选择，并为促进 GBM 患者的免疫治疗提供了潜力。
