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，只有长期存活者的轶事。 最近，免疫疗法已经看到针对各种类型的癌症的多次成功，但最近的几次失败是在癌症治疗中。 这种方式在GBM中的临床试验尚未成功。很明显，两个相互关联的因素， GBM的复杂免疫生物学阻碍了治疗效果：存在多种 免疫抑制机制和GBM微环境中显著的淋巴细胞耗竭。的 该计划项目的首要目标是解决T细胞活化不足和T细胞标记的问题。 GBM微环境中的细胞衰减。我们将检验总体假设，即促进CD 8 + CD 4 + T细胞功能可以克服GBM的高度免疫抑制机制。一 这一假设的推论是，免疫治疗组合的临床前和临床试验将提供 GBM治疗的有效方法。我们组建了一个高度互动和跨学科的团队 11名研究人员在4个高度综合的研究项目，由4个核心支持。这个团队（其中一些人） 已经合作了二十多年）带来了免疫生物学，神经， 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）中进行免疫治疗。我们建议 研究基于CD 161/Clec 2D（项目3）、IL-27和 内源性糖皮质激素信号传导（项目4），并了解如何克服这些问题，以改善 CD 4和CD 8效应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）， 生物计算/生物统计（核心2）和小鼠建模/成像（核心3）方法。 因此，该计划项目将为免疫抑制剂提供重要的机制见解。 GBM的微环境，进入如何激活T细胞对抗这些肿瘤的临床前途径， 用于靶向人类个性化GBM新抗原的新临床试验。

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.