人脑干胶质瘤中天然免疫蛋白MX1的表达对CD8+T淋巴细胞迁移的影响及相关分子机制

As the current therapy modalites for brainstem glioma are limited and the prognosis of patients is dismal. New therapy modalities are therefore urgently needed to improve patient outcomes. Immunotherapy such as anti-PD-1/PD-L1 therapy offers new chances for treatments for glioma patients. However, the outcome of clinical trials for anti-PD-1/PD-L1 therapies on brainstem glioma is not promising. It results from the low infiltration of CD8+ T lymphocytes within brainstem gliomas. The innate immune system plays a pivotal role in spontaneous infiltration of CD8+ T lymphocytes within tumor. Recently, the innate immune mechanisms have been applied to improve the outcome of anti-PD-1/PD-L1 therapy by it increasing the infiltration of CD8+ T lymphocytes within tumors. Our previous studies have revealed that the expression of an interferon induced protein-MX1 was associated with the high infiltration of CD8+ T lymphocytes within brainstem gliomas and the expression of MX1 in a human brainstem glioma cell line can promote the migration of CD8+ T lymphocytes in vitro. Based on the evidences and published studies, we hypothesize that the MX1 expression inside brainstem glioma cells can promote the migration and infiltration of CD8+ T lymphocytes via chemokines secretion. Therefore, we are trying to apply in-vitro experiment, in-vivo animal model and human tumor specimens to examine the effect and underlying mechanism of the MX1 expression within brainstem glioma cells on the migration of CD8+ T lymphocytes. The result of the study will provide a solid evidence to support further investigations on the MX1 expression on the outcome of anti-PD-1/PD-L1 therapy for brainstem glioma patients.

脑干胶质瘤治疗效果差，患者预后不良。针对PD-1/PD-L1的免疫治疗给脑干胶质瘤患者带来了希望，但中期结果显示大部分病人效果欠佳，这与脑干胶质瘤中缺乏CD8+T淋巴细胞浸润相关。通过天然免疫机制促进肿瘤内CD8+T淋巴细胞浸润，近来成为改善抗PD-1/PD-L1免疫治疗效果的重要途径。前期结果发现:天然免疫蛋白MX1高表达与脑干胶质瘤中CD8+T淋巴细胞浸润相关；高表达MX1的人脑干胶质瘤细胞在体外促进CD8+T淋巴细胞的趋化作用。结合既往文献，我们假设：脑干胶质瘤细胞内表达MX1蛋白可能通过分泌相关趋化因子来促进CD8+T淋巴细胞在肿瘤内浸润。本项目拟从体外实验、动物实验和病人标本三个层次研究MX1蛋白在脑干胶质瘤细胞内表达对CD8+T淋巴细胞趋化作用的影响和相关分子机制。研究可为下一步进行MX1表达协同抗PD-1/PD-L1治疗脑干胶质瘤的动物实验和未来可能的临床转化打好坚实基础。

针对PD-1/PD-L1的免疫治疗在大部分脑干胶质瘤病人效果欠佳，这与脑干胶质瘤中缺乏CD8+T淋巴细胞浸润相关。理解天然免疫通路促进肿瘤内CD8+T淋巴细胞浸润的机制对改善胶质瘤抗PD-1/PD-L1免疫治疗效果至关重要。本项目分别从人标本水平、体外细胞水平和动物水平研究胶质瘤中的天然免疫蛋白MX1表达对肿瘤内浸润Ｔ淋巴细胞的影响及相关分子机制。研究首先发现了MX1作为反映I类干扰素通路活性的分子，其在不同胶质瘤的表达中存在明显差异：MX1在高级别胶质瘤表达明显高于低级别胶质瘤，在IDH野生型胶质瘤中明显高于IDH突变型。MX1的表达与肿瘤组织内的CD8+/CD4+T 淋巴细胞浸润水平明显相关，MX1的表达与胶质瘤患者不良预后相关，MX1的表达水平能预测胶质瘤gp96疫苗免疫治疗效果；其次，通过MX1的敲除和过表达的体外细胞和动物学实验发现：MX1对胶质瘤的发生发展具有“双刃剑”作用。一方面MX1可能通过WNT-beta-Catenin通路促进胶质瘤上皮-间质转化，并促进胶质瘤细胞的增殖和侵袭；另一方面可能通过一种依赖于cGAS通路的I类干扰素正反馈机制，促进相关趋化因子的分泌，从而引起肿瘤内的CD8+/CD4+T淋巴细胞浸润。该项目发现了MX1在对胶质瘤治疗效果，特别是对肿瘤免疫治疗效果的预测价值，提示MX1可做为胶质瘤治疗预后标志物；同时发现了MX1分子本身对肿瘤细胞和免疫微环境的双重影响，揭示MX1既具有促进肿瘤细胞恶性进展的作用，同时可能通过促进胶质瘤内CD+和CD4+T细胞的浸润，而具有增强抗肿瘤免疫的作用。该工作可为天然免疫分子影响胶质瘤的发生发展以及抗胶质瘤免疫提供新的见解。