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首页> 外文期刊>Biology Open >CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression
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CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression

机译：CT-2A神经球源性高级别胶质瘤在小鼠中：解决肿瘤干细胞和免疫抑制的新模型

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Recently, several promising treatments for high-grade gliomas (HGGs) failed to provide significant benefit when translated from the preclinical setting to patients. Improving the animal models is fundamental to overcoming this translational gap. To address this need, we developed and comprehensively characterized a newin vivomodel based on the orthotopic implantation of CT-2A cells cultured in neurospheres (NS/CT-2A). Murine CT-2A methylcholanthrene-induced HGG cells (C57BL/6 background) were cultured in monolayers (ML) or NS and orthotopically inoculated in syngeneic animals. ML/CT-2A and NS/CT-2A tumors' characterization included the analysis of tumor growth, immune microenvironment, glioma stem cells (GSCs), vascularization and metabolites. The immuno-modulating properties of NS/CT-2A and ML/CT-2A cells on splenocytes were testedin vitro. Mice harboring NS/CT-2A tumors had a shorter survival than those harboring ML/CT-2A tumors (P=0.0033). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors showed more abundant GSCs (P=0.0002 and 0.0770 for Nestin and CD133, respectively) and regulatory T cells (Tregs,P=0.0074), and a strong tendency towards an increased vascularization (P=0.0503). There were no significant differences in metabolites' composition between NS/ and ML/CT-2A tumors.In vitro, NS were able to drive splenocytes towards a more immunosuppressive status by reducing CD8+T cells (P=0.0354) and by promoting Tregs (P=0.0082), macrophages (MF,P=0.0019) and their M2 subset (P=0.0536). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors show a more aggressive phenotype with increased immunosuppression and GSCs proliferation. Because of these specific features, the NS/CT-2A model represents a clinically relevant platform in the search for new HGG treatments aimed at reducing immunosuppression and eliminating GSCs.
机译：近来，当从临床前环境翻译成患者时，用于高级别神经胶质瘤（HGG）的几种有希望的治疗未能提供明显的益处。改善动物模型是克服这种翻译差距的基础。为了满足这一需求，我们基于在神经球（NS / CT-2A）中培养的CT-2A细胞的原位植入，开发并全面表征了一种新的体内模型。在单层（ML）或NS中培养小鼠CT-2A甲基胆碱诱导的HGG细胞（C57BL / 6背景），并在同系动物中原位接种。 ML / CT-2A和NS / CT-2A肿瘤的特征包括肿瘤生长，免疫微环境，神经胶质瘤干细胞（GSC），血管形成和代谢产物的分析。体外测试了NS / CT-2A和ML / CT-2A细胞对脾细胞的免疫调节特性。携带NS / CT-2A肿瘤的小鼠的生存期比携带ML / CT-2A肿瘤的小鼠的生存期短（P = 0.0033）。与标准ML / CT-2A肿瘤相比，NS / CT-2A肿瘤表现出更丰富的GSCs（巢蛋白和CD133分别为P = 0.0002和0.0770）和调节性T细胞（Tregs，P = 0.0074），并且有很强的血管形成增加（P = 0.0503）。 NS /和ML / CT-2A肿瘤之间的代谢产物组成没有显着差异。在体外，NS能够通过减少CD8 + T细胞（P = 0.0354）和促进Tregs来驱动脾细胞达到更高的免疫抑制状态。 P = 0.0082），巨噬细胞（MF，P = 0.0019）及其M2子集（P = 0.0536）。与标准的ML / CT-2A肿瘤相比，NS / CT-2A肿瘤表现出更具攻击性的表型，具有更高的免疫抑制和GSC增殖。由于这些特定的特征，NS / CT-2A模型代表了临床相关平台，用于寻找旨在减少免疫抑制和消除GSC的新型HGG治疗。

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