Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, The University of Sydney Northern Clinical School and Northern Sydney Local Health District, St Leonards, NSW, Australia.
Sydney Vital Translational Research Centre, Royal North Shore Hospital, St Leonards, NSW, Australia.
PLoS One. 2020 Apr 2;15(4):e0226444. doi: 10.1371/journal.pone.0226444. eCollection 2020.
Glioblastoma, the most aggressive form of glioma, has a 5-year survival rate of <5%. While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. This study quantifies the temporal and spatial localization of immune cell populations and mediators during glioma development. Eight-week old male C57Bl/6 mice were orthotopically inoculated with 1x106 Gl261 cells and tumor morphology, local and systemic immune cell populations, and plasma cytokines/chemokines assessed at day 0, 1, 3, 7, 14, and 21 post-inoculation by magnetic resonance imaging, chromogenic immunohistochemistry, multiplex immunofluorescent immunohistochemistry, flow cytometry and multiplex immunoassay respectively. From day 3 tumors were distinguishable with >30% Ki67 and increased tissue vascularization (p<0.05). Increasing tumor proliferation/malignancy and vascularization were associated with significant temporal changes in immune cell populations within the tumor (p<0.05) and systemic compartments (p = 0.02 to p<0.0001). Of note, at day 14 16/24 plasma cytokine/chemokines levels decreased coinciding with an increase in tumor cytotoxic T cells, natural killer and natural killer/T cells. Data derived provide baseline characterization of the local and systemic immune response during glioma development. They reveal that type II macrophages and myeloid-derived suppressor cells are more prevalent in tumors than regulatory T cells, highlighting these cell types for further therapeutic exploration.
胶质母细胞瘤是最具侵袭性的神经胶质瘤，其 5 年生存率<5%。虽然在 Gl261 胶质母细胞瘤模型中经常研究放射和免疫疗法，但对其固有免疫反应知之甚少。本研究定量分析了免疫细胞群和介质在神经胶质瘤发展过程中的时空定位。将 1x106 Gl261 细胞原位接种于 8 周龄雄性 C57Bl/6 小鼠，通过磁共振成像、显色免疫组化、多重免疫荧光免疫组化、流式细胞术和多重免疫分析，分别在接种后第 0、1、3、7、14 和 21 天评估肿瘤形态、局部和全身免疫细胞群以及血浆细胞因子/趋化因子。从第 3 天开始，肿瘤的 Ki67 阳性率超过 30%，组织血管化增加（p<0.05）。肿瘤增殖/恶性程度和血管化的增加与肿瘤内（p<0.05）和全身（p=0.02 至 p<0.0001）免疫细胞群的时间变化显著相关。值得注意的是，在第 14 天，24 种血浆细胞因子/趋化因子水平下降，同时肿瘤细胞毒性 T 细胞、自然杀伤细胞和自然杀伤/T 细胞增加。所得数据提供了神经胶质瘤发展过程中局部和全身免疫反应的基线特征。它们表明，与调节性 T 细胞相比，II 型巨噬细胞和髓系来源的抑制细胞在肿瘤中更为普遍，这突出了这些细胞类型进一步的治疗探索。
