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.

抽象的免疫系统激活无法控制和消除癌症的潜力更多急性需要的是胶质母细胞瘤（GBM）患者；成功使用免疫肿瘤（IO）药物消除GBM将是变革性的。了解如何影响GBM中的抗肿瘤免疫力其独特的微环境的功能，其中包括独特的脑外基质（ECM）和副脑屏障保护对成功至关重要。同样重要的是患者最常出现需要快速治疗的关键症状，通常是手术放射疗法，因此在IO药物的添加如何与效果相交的角度提出了挑战先前的治疗。在这里，我们假设转化生长因子β（TGFβ）是原发性GBM的深刻免疫抑制肿瘤微环境（TME）。此外，这个免疫抑制性TME通过护理标准，放射疗法永久存在。我们假设高水平 TGFβ活性分别通过分别增加了细胞组成和生物力学特性髓样衍生的抑制细胞（MDSC）的存在，并诱导僵硬的透明质酸和富含Tenascin的ECM 激活整联蛋白和局灶性粘合剂激酶（FAK）。这种机构病理学提高到更大 TGFβ激活，增加刚度和活化的FAK，所有这些都会促进免疫抑制髓样细胞该警戒线以防止T细胞渗透。此外，对手术的反应并加强了这一点生物学，因为两者都会诱导TGFβ激活，从而进一步“僵硬”复发性TME。这个恶性循环必须被中断以实现GBM中T细胞浸润和有效的免疫响应。我们建议使用免疫胜任的鼠模型，这些模型概括了关键的GBM特征，以研究TGFβ培养基如何机械病理学和免疫响应，提供TME重塑作为TGFβ的详细分析辐射后，并将这些机制转化为理论策略以重新定义免疫景观为了更大的回应IO。我们的具体目的是：1。测试阻断TGFβ是否可以破坏永久性的原发性和复发性GBM的免疫抑制机理病理学，并促进对颅内合成小鼠模型中的辐射和随后的免疫疗法。 2。评估生物力学，MDSC，T细胞活性和ECM组成之间的相关性与治疗和 TGFβ抑制。 3。确定机理促进GBM的特定机制免疫抑制。通过应用机械临床前研究产生的发现，我们翻译目标是将TME从一个有效免疫疗法的障碍的TME重新定位到一个障碍。有助于人类成功的抗肿瘤免疫。

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.