Reorienting the Glioblastoma Microenvironment to Respond to Immunotherapy

重新调整胶质母细胞瘤微环境以响应免疫治疗

基本信息

批准号：
10554364
负责人：
Mary Helen Barcellos-Hoff
金额：
$ 57.51万
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：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554364
关键词：
Acute Affect Biology Biomechanics Blood - brain barrier anatomy Brain CD14 gene Cell Survival Cerebrospinal Fluid Cessation of life Clinical Data Diagnosis Disease Excision Exhibits Extracellular Matrix Failure Feeds Focal Adhesion Kinase 1 Focal Adhesions Fostering Genetic Transcription Genetically Engineered Mouse Glioblastoma Glioma Human Hyaluronan Immune Immune checkpoint inhibitor Immune response Immune system Immunocompetent Immunologic Memory Immunooncology Immunosuppression Immunotherapy Integrins Interruption Knowledge Ligands Link Malignant Neoplasms Mediating Messenger RNA Modeling Mutation Myeloid-derived suppressor cells Nivolumab Operative Surgical Procedures Organ PD-1 inhibitors Patients Pharmaceutical Preparations Phenotype Prognosis Property Publishing Radiation Radiation therapy Recurrence Recurrent tumor Signal Transduction Spinal Neoplasms Symptoms T cell infiltration T-Cell Proliferation T-Lymphocyte TGFB1 gene Tenascin Testing Therapeutic Transforming Growth Factor beta Translating Tumor Immunity Work cancer cell cancer type chemotherapy glioma cell line mechanical properties monocyte mouse model novel strategies phase III trial preclinical study pressure prevent radiation response receptor response standard of care success temozolomide tumor tumor microenvironment tumor-immune system interactions

项目摘要

Abstract Nowhere is the potential for immune system activation to control and potentially eliminate cancer more acutely needed than in glioblastoma (GBM) patients; successful use of immuno-oncology (IO) drugs to eliminate GBM would be transformative. Understanding how to influence anti-tumor immunity in GBM as a function of its unique microenvironment, which includes the uniquely constituted brain extracellular matrix (ECM) and the blood-brain barrier protection of parenchyma, is critical to success. Equally important is that patients most often present with critical symptoms that require rapid treatment, usually surgery followed by radiation therapy, thus presenting a challenge in terms of how addition of IO drugs will intersect with the effects of prior treatment. Here we hypothesize that transforming growth factor β (TGFβ) is at the root of the profoundly immunosuppressive tumor microenvironment (TME) of primary GBM. Furthermore, this immunosuppressive TME is perpetuated by standard of care, radiation therapy. We postulate that high levels of TGFβ activity affect the cellular composition and biomechanical properties by respectively, increasing the presence of myeloid derived suppressor cells (MDSC) and inducing a stiff, hyaluronan and tenascin rich ECM that activates integrins and focal adhesion kinase (FAK). This mechanopathology feeds forward to greater TGFβ activation, increased stiffness and activated FAK, all of which foster immunosuppressive myeloid cells that cordon off GBM to prevent T-cell infiltration. Moreover, the response to surgery and RT reinforce this biology because both induce TGFβ activation that further ‘stiffens’ the recurrent TME. This vicious cycle must be interrupted to achieve T-cell infiltration and effective immune response in GBM. We propose to use immune competent murine models that recapitulate key GBM features to investigate how TGFβ mediates mechanopathology and immune response, provide detailed analysis of TME remodeling as a function of TGFβ after radiation, and translate these mechanisms into therapeutic strategies to re-orient the immune landscape for greater response to IO. Our specific aims are to: 1. Test whether blocking TGFβ can disrupt the cycle that perpetuates immunosuppressive mechanopathology of primary and recurrent GBM and promote response to radiation and subsequent immunotherapy in intracranial syngeneic mouse models. 2. Evaluate the correlations among biomechanics, MDSC, T cell activity and ECM composition as a function of treatment and TGFβ inhibition. 3. Determine the specific mechanisms by which mechanopathology promote GBM immunosuppression. By applying the discoveries generated from mechanistic preclinical studies, our translational objective is to reorient the TME from one that is a barrier to effective immunotherapy to one that aids successful anti-tumor immunity in humans.

抽象的没有什么比激活免疫系统更有可能控制和消除癌症了比胶质母细胞瘤 (GBM) 患者更需要成功使用免疫肿瘤 (IO) 药物；消除 GBM 将具有变革意义。其独特的微环境的功能，其中包括独特构成的大脑细胞外基质 (ECM) 和血脑屏障对实质的保护，对于成功同样重要。患者最常出现严重症状，需要快速治疗，通常是手术治疗，然后再进行治疗放射治疗，因此在添加 IO 药物如何与效果相交叉方面提出了挑战在此我们追寻转化生长因子β（TGFβ）是该疾病的根源。原发性 GBM 的肿瘤微环境（TME）具有显着的免疫抑制作用。我们假设高水平的护理和放射治疗会导致免疫抑制性 TME 持续存在。 TGFβ活性的影响细胞组成和生物力学特性，分别通过增加骨髓源性抑制细胞 (MDSC) 的存在并诱导僵硬、富含透明质酸和生腱蛋白的 ECM 激活整合素和粘着斑激酶 (FAK) 这种机械病理学可促进更大的作用。 TGFβ 激活、硬度增加和 FAK 激活，所有这些都会促进免疫抑制性骨髓细胞封锁GBM以防止T细胞浸润此外，对手术和放疗的反应强化了这一点。生物学上，因为两者都会诱导 TGFβ 激活，从而进一步“强化”复发性 TME，这种恶性循环必然存在。中断以实现 GBM 中的 T 细胞浸润和有效的免疫反应。具有免疫能力的小鼠模型，可概括 GBM 的关键特征，以研究 TGFβ 如何介导机械病理学和免疫反应，提供 TME 重塑作为 TGFβ 功能的详细分析放射后，并将这些机制转化为治疗策略，以重新定位免疫景观为了更好地应对 IO，我们的具体目标是： 1. 测试阻断 TGFβ 是否会破坏该循环。维持原发性和复发性 GBM 的免疫抑制机械病理学并促进对 2. 评估颅内同基因小鼠模型中的放射治疗和随后的免疫治疗。生物力学、MDSC、T 细胞活性和 ECM 成分之间的相关性作为治疗和治疗的函数 3. 确定机械病理学促进 GBM 的具体机制。通过应用机械临床前研究的发现，我们转化目标是将 TME 从阻碍有效免疫治疗的障碍重新定位为阻碍有效免疫治疗的障碍有助于人类成功的抗肿瘤免疫力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Positron Emission Tomography Imaging of Functional Transforming Growth Factor β (TGFβ) Activity and Benefit of TGFβ Inhibition in Irradiated Intracranial Tumors.

DOI：
10.1016/j.ijrobp.2020.09.043
发表时间：
2021-02-01
期刊：
International journal of radiation oncology, biology, physics
影响因子：
0
作者：
Gonzalez-Junca A;Reiners O;Borrero-Garcia LD;Beckford-Vera D;Lazar AA;Chou W;Braunstein S;VanBrocklin H;Franc BL;Barcellos-Hoff MH
通讯作者：
Barcellos-Hoff MH

Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.