免疫微环境调控贝伐单抗促脑胶质瘤侵袭的分子机制

Brain glioma is the most common primary malignant tumor in central nervous system with very poor prognosis. Patients respond minimally to currently used therapies, including surgical resection, radiation and chemotherapy. Progression-free survival was prolonged in patients with newly diagnosed or recurrent glioblastoma by anti-angiogenic therapy with bevacizumab, a recombinant monoclonal antibody to human vascular endothelial growth factor. However, enhanced tumor invasion was also observed after bevacizumab treatment. The mechanism of bevacizumab-induced glioma invasion is unclear. Tumor associated microglia and macrophages (TAMs) are the major cells in immune microenvironment of brain glioma. TAMs play important roles in the development and progress of glioma. Whether TAMs involve in the process of bevacizumab-induced glioma invasion is unclear. Our previous study showed that induction of Pyk2 activation involved in this process. As scaffolding proteins, focal adhesion kinase (FAK) and its family member Pyk2 regulate cytokine secretion through MAPK and other signaling pathways, then recruit and activate microglia and macrophages. Therefore, this study will investigate the effect of bevacizumab on TAMs infiltration, proliferation, polarization and cytokine secretion in immune microenvironment in in vivo animal intracranial glioma model. The molecular mechanisms of interactions between glioma cells and TAMs will be explored in cell co-culture system. Then, the role of immune microenvironment and FAK/Pyk2-mediated signaling pathways in bevacizumab-induced glioma invasion will be further studied in transgenic mouse xenografts. The results of this research will provide a new rationale for exploring the combined anti-angiogenic therapy with immunotherapy for human brain glioma.

脑胶质瘤是最常见的原发性中枢神经系统恶性肿瘤，预后极差。抗血管生成药物贝伐单抗虽可改善胶质瘤患者的无进展生存期，但临床治疗后胶质瘤的侵袭能力增强，其作用机制还有待阐明。胶质瘤相关的小胶质/巨噬细胞(TAMs)是其免疫微环境的主要成分，影响着肿瘤的发生发展，但TAMs对贝伐单抗促胶质瘤侵袭的调节作用尚不清楚。申请者前期结果发现粘着斑激酶(FAK)家族成员Pyk2与贝伐单抗诱导的胶质瘤侵袭有关。FAK/Pyk2可以通过MAPK等信号通路促使细胞分泌趋化因子，进而募集和活化小胶质/巨噬细胞。本项目拟采用细胞共培养和动物模型，观察贝伐单抗治疗对免疫微环境中TAMs浸润、增殖、极化、炎症反应等功能的影响，探讨脑胶质瘤细胞与TAMs相互影响的信号分子机制，进而在转基因小鼠模型中验证免疫微环境及FAK/Pyk2介导的信号通路在贝伐单抗促胶质瘤侵袭中的作用，为脑胶质瘤联合靶向治疗药物的研发提供理论基础。

脑胶质瘤是最常见的原发性中枢神经系统恶性肿瘤，预后极差。抗血管生成药物贝伐单抗虽可改善胶质瘤患者的无进展生存期，但临床治疗后胶质瘤的侵袭能力增强，其作用机制还有待阐明。胶质瘤相关的小胶质/巨噬细胞(TAMs)是其免疫微环境的主要成分，影响着肿瘤的发生发展，但TAMs对贝伐单抗促胶质瘤侵袭的调节作用尚不清楚。本项目在细胞共培养和动物模型，观察贝伐单抗治疗对免疫微环境中TAMs浸润、增殖、极化、炎症反应等功能的影响，并探讨脑胶质瘤细胞与TAMs相互影响的信号分子机制。本项目研究结果显示：贝伐单抗治疗初期瘤内浸润TAMs早期以M1型为主，后期则以M2型为主，TAMs这种功能状态的改变与贝伐单抗促进胶质瘤细胞分泌CSF-1有关；而M2型TAMs通过调控胶质瘤细胞Pyk2信号通路而促使瘤细胞发生侵袭。近年来，血管紧张素受体抑制剂在中枢神经系统疾病中的作用也逐渐受到关注。本项目也进一步证实血管紧张素受体抑制剂替米沙坦可以调控小胶质细胞的极化状态，这也为脑胶质瘤贝伐单抗联合用药提供了实验基础的新思路。贝伐单抗联合替米沙坦能否更有效发挥抗肿瘤作用有待于进一步的研究。