Understanding and Overcoming T cell Immunosuppression in Glioblastoma

摘要 胶质母细胞瘤(GBM)仍然是一种难以治疗的癌症，只有长期幸存者的轶事例子。 最近，免疫疗法在治疗各种类型的癌症方面取得了多项成功，但最近有几项 这种方法在GBM中的临床试验尚未成功。很明显，两个相互关联的因素 GBM复杂的免疫生物学阻碍了治疗效果：存在多发性 免疫抑制机制和GBM微环境中显著的淋巴枯竭。这个 该计划项目的总体目标是解决T细胞活化不足和标记T细胞的问题 基底膜微环境中的细胞衰减。我们将检验推广CD8的总体假设 CD4T细胞功能可以克服GBM的高度免疫抑制机制。一个 这一假设的推论是，免疫疗法组合的临床前和临床试验将提供 治疗基底膜的有效方法。我们组建了一支高度互动和跨学科的团队 在4个高度整合的研究项目中的11名调查人员，由4个核心提供支持。这支球队(其中一些人 在一起工作了二十多年)带来了免疫生物学、神经学- 肿瘤学、临床试验、基因组学和计算分析来机械地研究这两个关键因素。 我们计划研究免疫检查点阻断如何与其他T细胞激活相结合 在临床试验(项目1)和临床前小鼠模型(项目2)中的免疫疗法。我们建议 基于CD161/Clec2D(Project 3)、IL-27和IL-27的人肾小球系膜细胞免疫抑制途径研究 内源性糖皮质激素信号(项目4)，并了解如何克服这些信号以改善 CD4和CD8效应性T细胞的抗肿瘤功能核心服务将提供复杂的基因组(核心1)， 这些项目的生物计算/生物统计学(核心2)和老鼠建模/成像(核心3)方法。 因此，该计划项目将为免疫抑制提供重要的机械性见解 GBM的微环境，进入临床前途径，如何激活T细胞对抗这些肿瘤，最终 进入一项新的临床试验，以靶向人类个性化的GBM新抗原。

Abstract Glioblastoma (GBM) remains a formidable cancer to treat with only anecdotal examples of long-term survivors. Recently, immunotherapy has seen multiple successes against various types of cancer, but several recent clinical trials of this modality in GBM have not been successful. It is evident that two inter-related factors in the complex immunobiology of GBM have thwarted therapeutic efficacy: the existence of multiple immunosuppressive mechanisms and the significant lymphodepletion in the GBM microenvironment. The overarching goal of the Program Project is to address the problem of insufficient T cell activation and marked T cell attenuation in the GBM microenvironment. We will test the overall hypothesis that promotion of CD8+ and CD4+ T cell functionality can overcome the highly immunosuppressive mechanisms of GBM. A corollary to this hypothesis is that preclinical and clinical trials of immunotherapy combinations will provide an effective approach to GBM treatment. We have assembled a highly interactive and interdisciplinary team of 11 investigators in 4 highly integrated Research Projects, supported by 4 Cores. This team (some of whom have been working together for more than two decades) brings deep expertise in immunobiology, neuro- oncology, clinical trials, genomics and computational analyses to mechanistically study these two critical factors. We plan to study how immune checkpoint blockade can be combined with other T cell activating immunotherapies both in a clinical trial (Project 1) and in preclinical mouse models (Project 2). We propose to study novel immunosuppressive pathways in human GBMs based on CD161/ Clec2D (Project 3), IL-27 and endogenous glucocorticoid signaling (Project 4) and understand how these can be overcome to improve the anti-tumor function of CD4 and CD8 effector T cells. Core services will provide sophisticated genomic (Core 1), biocomputational/ biostatistical (Core 2), and mouse modeling/ imaging (Core 3) approaches to these Projects. This Program Project will thus provide significant mechanistic insights into the immunosuppressive microenvironment of GBM, into preclinical avenues of how to activate T cells against these tumors and finally into a novel clinical trial to target personalized GBM neoantigens in humans.