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

• 批准号: 10093157
• 负责人: Mary Helen Barcellos-Hoff
• 金额: $ 59.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093157
• 关键词: Acute; Affect; Biology; Biomechanics; Blood - brain barrier anatomy; Brain; CD14 gene; Cell Survival; Cerebrospinal Fluid; Cessation of life; Characteristics; Clinical; Complement Factor B; 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; Plant Roots; Prognosis; Property; Publishing; Radiation; Radiation therapy; Recurrence; Recurrent tumor; Signal Transduction; Spinal Neoplasms; Symptoms; T-Cell Proliferation; T-Lymphocyte; TGFB1 gene; Tenascin; Testing; Therapeutic; Transforming Growth Factors; Translating; Tumor Immunity; Tumor-infiltrating immune cells; Work; cancer cell; cancer type; chemotherapy; glioma cell line; mechanical properties; monocyte; mouse model; novel strategies; phase III trial; preclinical study; pressure; prevent; programs; radiation response; receptor; response; standard of care; success; temozolomide; tumor; tumor microenvironment; tumor-immune system interactions

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.

摘要 免疫系统激活控制和潜在消除癌症的潜力无处不在 比胶质母细胞瘤（GBM）患者更迫切需要;成功使用免疫肿瘤学（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， 其独特的微环境，其中包括独特构成的脑细胞外基质的功能 (ECM)以及实质的血脑屏障保护是成功的关键。同样重要的是 患者最常出现需要快速治疗的危急症状，通常是手术， 放射治疗，因此提出了一个挑战，在如何添加IO药物将与影响交叉 之前的治疗。在这里，我们假设转化生长因子β（TGFβ）是肿瘤的根源。 原发性GBM的深度免疫抑制肿瘤微环境（TME）。而且这 免疫抑制性TME通过标准护理、放射疗法而持续存在。我们假设高水平的 TGFβ活性的变化分别通过增加细胞的生物力学性能和细胞的组成来影响细胞的生物力学性能。 存在髓源性抑制细胞（MDSC）并诱导坚硬的、富含透明质酸和腱生蛋白的ECM 激活整合素和粘着斑激酶（FAK）。这种机械病理学会导致更大的 TGFβ激活、僵硬度增加和活化的FAK，所有这些都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RT的反应强化了这一点。 因为两者都诱导TGFβ活化，进一步“硬化”复发性TME。这种恶性循环必须 中断以实现GBM中的T细胞浸润和有效的免疫应答。我们建议使用 概括关键GBM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的函数的详细分析 并将这些机制转化为治疗策略，以重新定位免疫景观 对IO的响应更大。我们的具体目标是：1.测试阻断TGFβ是否可以破坏 维持原发性和复发性GBM的免疫抑制机制病理学，并促进对 放射和随后的免疫治疗。2.评价 生物力学、MDSC、T细胞活性和ECM组成之间的相关性作为治疗的函数， TGFβ抑制。3.确定机械病理学促进GBM的具体机制 免疫抑制通过应用从机制临床前研究中产生的发现， 翻译的目的是重新定位TME，从一个有效的免疫治疗的障碍， 有助于人类成功的抗肿瘤免疫。