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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：
10339330
负责人：
Mary Helen Barcellos-Hoff
金额：
$ 57.54万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339330
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

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.

摘要