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.

项目摘要胶质母细胞瘤（GBM）是成年人中最常见的原发性恶性脑肿瘤，是普遍致命的尽管多模式处理。因此，新颖的疗法至关重要。免疫疗法，例如到目前为止，检查点封锁未能证明临床功效。 GBM具有较高的内在电阻除其他因素外，抗肿瘤的免疫力低下，MHC-I表达低和缺乏T细胞浸润。需要促进GBM免疫原性以使肿瘤对检查点疗法的敏感性。蛋白质磷酸酶2a（PP2A）是一种无处不在的丝氨酸/苏氨酸磷酸酶，由催化（C），调节（B）组成和脚手架（a）亚基。我们以前已经报道过，PP2AC的药理抑制可以增强抗PD1阻断在包括GBM在内的多个临床前模型中的功效。但是，机制或尚不清楚负责增强抗肿瘤免疫反应的细胞类型。最近，我们发现胶质瘤细胞中PP2AC的缺乏，通过遗传修饰导致了干扰素信号的增强，这会增强。对于引发抗肿瘤免疫反应至关重要。神经胶质瘤细胞中PP2A缺乏增强了MHC-I表达，肿瘤T细胞浸润和对体内检查点阻滞的敏感性。我们还证明了PP2AC 缺乏导致细胞质双链DNA（DSDNA）的产生增强，已知会激活 CGAS-sting信号传导，这是干扰素产生的有效模拟器。而且，从所有人的公正筛选中已知的调节B亚基，我们确定了PP2A的特定B亚基PPP2R2C具有与 PP2AC促进MHC-I表达。在这个项目中，我们将首先阐明PP2AC缺陷的影响胶质瘤细胞在肿瘤微环境的免疫学景观上，将鉴定免疫细胞负责PP2AC调制抗肿瘤免疫力的类型。然后，我们将剖析分子机制该将PP2A缺乏症与CGAS插入激活和神经胶质瘤中干扰素信号的促进微环境。我们还将确定特定的调节B亚基PPP2R2C在调节中的作用 DSDNA的产生和CGAS-sting信号传导。最后，我们将研究PP2AC缺乏症的能力增强放射疗法的治疗疗效，当前护理标准的主要组成部分和A CGAS刺信信号的已知刺激器。该项目的直接目标是确定 PP2A在GBM中调节免疫原性，其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。我们认为这项研究符合Ninds的使命寻求对神经系统的基本知识，并利用这些知识来减轻神经疾病，例如脑肿瘤。