Regulation of Tumor Immunogenicity in Glioblastoma

胶质母细胞瘤肿瘤免疫原性的调节

基本信息

批准号：
10638755
负责人：
Sze Chun Winson Ho
金额：
$ 45.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638755
关键词：
Address Adult Brain Neoplasms CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cells Clinical Clinical Trials Combined Modality Therapy Cross Presentation Cytoplasm DNA DNA Damage Data Dendritic Cells Disease Effectiveness Genetic Glioblastoma Glioma Goals Human Immune Immune response Immunocompetent Immunocompromised Host Immunologics Immunotherapy Impairment In Vitro Infiltration Inflammatory Interferon Type I Interferons Knock-out Knowledge Macrophage Malignant Neoplasms Malignant neoplasm of brain Mediating Mission Modeling Modification Molecular Mus National Institute of Neurological Disorders and Stroke Natural Immunity Nature Nervous System Operative Surgical Procedures PD-1 blockade Pathway interactions Patients Phosphoric Monoester Hydrolases Pre-Clinical Model Production Protein Inhibition Protein Subunits Protein phosphatase Radiation Radiation therapy Radiosensitization Regulation Reporting Resistance Role Serine Signal Transduction Small Interfering RNA Stimulator of Interferon Genes Substrate Specificity T cell infiltration T-Cell Activation Therapeutic Threonine Treatment Efficacy Tumor Immunity Tumor Promotion adaptive immunity aggressive therapy anti-tumor immune response brain shape cancer infiltrating T cells cell type checkpoint therapy chemotherapy clinical efficacy ds-DNA immune checkpoint blockade immunogenicity in vivo insight link protein neoplastic cell nervous system disorder new therapeutic target novel novel therapeutics pharmacologic pre-clinical response scaffold screening side effect single-cell RNA sequencing small molecule inhibitor standard of care synergism tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is the most common primary malignant brain tumor in adults that is universally fatal despite multimodal treatment. Novel therapies are therefore critically needed. Immunotherapy, such as checkpoint blockade, has thus far failed to demonstrate clinical efficacy. GBM has high intrinsic resistance to antitumor immunity due to, among other factors, low expression of MHC-I and lack of T-cell infiltration. Strategies to promote immunogenicity of GBM to sensitize tumor to checkpoint therapy is needed. Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase comprised of a catalytic (C), regulatory (B) and scaffolding (A) subunit. We have previously reported that pharmacological inhibition of PP2Ac can enhance the efficacy of anti-PD1 blockade in multiple preclinical models, including GBM. However, the mechanism(s) or cell type(s) responsible for the enhanced antitumor immune response is not well understood. Recently, we found that deficiency of PP2Ac, by genetic modification, in glioma cells resulted in enhanced interferon signaling, which is essential to eliciting antitumor immune response. PP2A deficiency in glioma cells enhanced MHC-I expression, tumor T-cell infiltration and sensitivity to checkpoint blockade in vivo. We also demonstrated that PP2Ac deficiency led to enhanced production of cytoplasmic double-stranded DNA (dsDNA), which is known to activate cGAS-STING signaling, a potent simulator of interferon production. Moreover, from unbiased screening of all known regulatory B subunits, we identified PPP2R2C, a specific B subunit of PP2A, to have a similar role as PP2Ac in promoting MHC-I expression. In this project, we will first elucidate the effect of PP2Ac deficiency in glioma cells on the immunological landscape of the tumor microenvironment and will identify the immune cell types responsible for PP2Ac modulated antitumor immunity. We will then dissect the molecular mechanisms that link PP2A deficiency to cGAS-STING activation and promotion of interferon signaling in the glioma microenvironment. We will also identify the role of the specific regulatory B subunit, PPP2R2C, in modulating dsDNA production and cGAS-STING signaling. Finally, we will investigate the ability of PP2Ac deficiency to enhance the therapeutic efficacy of radiation therapy, a major component of current standard-of-care and a known stimulator of cGAS-STING signaling. The immediate goal of this project is to identify the mechanisms of PP2A modulated immunogenicity in GBM, with the long-term goal of developing precise PP2A targeting strategies to increase effectiveness of immunotherapies for GBM. We believe this study fits the mission of NINDS to seek fundamental knowledge of the nervous system and to use that knowledge to reduce the burden of neurological disease such as brain tumor.

项目概要胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤，通常是致命的尽管采用多模式治疗。因此，迫切需要新的疗法。免疫疗法，例如检查点封锁，迄今为止未能证明临床疗效。 GBM 具有很高的内在抵抗力 MHC-I 低表达和缺乏 T 细胞浸润等因素导致抗肿瘤免疫。需要促进 GBM 免疫原性的策略，以使肿瘤对检查点治疗敏感。蛋白质磷酸酶 2A (PP2A) 是一种普遍存在的丝氨酸/苏氨酸磷酸酶，由催化 (C) 和调节 (B) 组成和脚手架 (A) 亚基。我们之前报道过 PP2Ac 的药理抑制可以增强抗 PD1 阻断在多种临床前模型（包括 GBM）中的功效。然而，机制或负责增强抗肿瘤免疫反应的细胞类型尚不清楚。最近，我们发现通过基因改造，神经胶质瘤细胞中 PP2Ac 的缺乏导致干扰素信号传导增强，从而对于引发抗肿瘤免疫反应至关重要。神经胶质瘤细胞中 PP2A 缺陷增强了 MHC-I 表达，肿瘤 T 细胞浸润和体内检查点阻断的敏感性。我们还证明了 PP2Ac 缺乏导致细胞质双链 DNA (dsDNA) 的产生增强，众所周知，dsDNA 可以激活 cGAS-STING 信号传导，干扰素产生的有效模拟器。此外，通过对所有已知调节 B 亚基，我们确定了 PPP2R2C（PP2A 的一个特定 B 亚基）具有与 PP2Ac 促进 MHC-I 表达。在这个项目中，我们将首先阐明 PP2Ac 缺乏对神经胶质瘤细胞在肿瘤微环境的免疫景观中，并将识别免疫细胞负责 PP2Ac 调节抗肿瘤免疫的类型。然后我们将剖析分子机制将 PP2A 缺陷与神经胶质瘤中 cGAS-STING 激活和干扰素信号传导促进联系起来微环境。我们还将确定特定调节 B 亚基 PPP2R2C 在调节中的作用 dsDNA 产生和 cGAS-STING 信号传导。最后，我们将研究 PP2Ac 缺乏症的能力提高放射治疗的治疗效果，放射治疗是当前护理标准的主要组成部分，已知的 cGAS-STING 信号传导刺激剂。该项目的近期目标是确定 PP2A 调节 GBM 中的免疫原性，长期目标是开发精确的 PP2A 靶向提高 GBM 免疫疗法有效性的策略。我们相信这项研究符合 NINDS 的使命寻求神经系统的基础知识并利用这些知识来减轻神经系统的负担神经系统疾病，例如脑肿瘤。