靶向Treg的GITR增敏胶质瘤免疫治疗的机制研究

Glioblastoma is a highly malignant brain tumor. Traditional anti-tumor therapies provide limited benefit for patients with this dismal disease. Based on the encouraging response of programmed cell death 1 (PD-1) inhibitor in other solid tumors, immuotherapy is regarded as a promising way for treating glioma. However, a Phase III clinical trial reported an unfavorable outcome of PD-1 inhibitor in GBM patients. And we also find it did not play its expected anti-tumor role in our mouse model of primary glioma in our previous study. .Regulatory T-cells (Tregs) is an indispensable factor for tumor immunosuppression. In our previous study, we found out the increasing amount of FoxP3+ Tregs in tumor microenvironment was associated with the higher malignant behavior and the worse prognosis. Glucocorticoid-induced tumor necrosis factor receptor related protein (GITR) is regularly expressed on Tregs. And combined treatment of GITR agonist and PD-1 inhibitor can significantly improve survival in our primary mouse glioma model. According to the previous results of our study, Ligation of GITR on Tregs can increase the transcriptional activities of NF-κB and STAT6, as well as decrease the cytokine expression of IL-6 and IL-10. Therefore, we hypothesize that combining immunotherapies of anti-PD-1 that turns on tumor specific effector T-cells with an anti-GITR that modifies immunosuppressive tumor microenvironment, represents a rational approach to fight this dismal disease. In this study, we will test our hypothesis in vitro and in patient-derived xenograft (PDX) mouse model, and verify the molecular mechanism of the combining immunotherapies. We believe our study will provide the theoretical basis and data support for the development of new immunotherapy strategies in clinical practice.

胶质母细胞瘤是最常见的原发脑恶性肿瘤，即使手术、放疗及化疗，预后仍极差，免疫治疗是研究热点，而如何改变肿瘤内免疫抑制微环境是免疫治疗成功的关键，Treg细胞被认为是胶质瘤免疫抑制的重要因素，我们前期研究证明；随着胶质瘤恶性程度增加，Treg细胞浸润越明显，预后越差；Treg能增加M2型巨噬细胞的比例，同时抑制T细胞免疫，降低免疫治疗的疗效；进一步发现GITR的激动剂能改变Treg细胞免疫抑制的功能，与PD-1抗体联用能提高原发胶质瘤小鼠的生存期，并且GITR激动剂能提高Treg中NF-κB及STAT6转录活性，降低IL-6、IL-10的分泌，但其具体增敏机制值得探讨。本项目拟通过原代细胞分离、共培养、RNA测序、PDX模型等方式，阐明靶向Treg上GITR如何改变免疫微环境，增加胶质瘤对PD-1抗体的敏感性的机制，为提高胶质瘤免疫治疗疗效提供理论依据。

胶质母细胞瘤是最常见的原发脑恶性肿瘤，即使手术、放疗及化疗，预后仍极差，免.疫治疗是研究热点，而如何改变肿瘤内免疫抑制微环境是免疫治疗成功的关键，Treg细胞.被认为是胶质瘤免疫抑制的重要因素，我们前期研究证明；随着胶质瘤恶性程度增加，Tr.eg细胞浸润越明显，预后越差；Treg能增加M2型巨噬细胞的比例，同时抑制T细胞免疫，.降低免疫治疗的疗效；进一步发现GITR的激动剂能改变Treg细胞免疫抑制的功能，与PD-1.抗体联用能提高原发胶质瘤小鼠的生存期，并且GITR激动剂能提高Treg中NF-κB及STAT6.转录活性，降低IL-6、IL-10的分泌，但其具体增敏机制值得探讨。本项目拟通过原代细.胞分离、共培养、RNA测序、PDX模型等方式，阐明靶向Treg上GITR如何改变免疫微环境，.增加胶质瘤对PD-1抗体的敏感性的机制，为提高胶质瘤免疫治疗疗效提供理论依据。

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