Role of FAP-positive cells in immune response to irradiated glioblastoma

FAP 阳性细胞在放射胶质母细胞瘤免疫反应中的作用

基本信息

批准号：
10649237
负责人：
Claire Isabelle Vanpouille-Box
金额：
$ 23.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2023-04-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649237
关键词：
Abscopal effect Adult Alpha Cell Brain Brain Neoplasms Breast Cancer Model CD8-Positive T-Lymphocytes CD8B1 gene Carcinoma Cells Colorectal Cancer Data Disease Effector Cell Exclusion Exhibits FDA approved Fibroblasts Flow Cytometry Gene Expression Profile Glioblastoma Human ITGAX gene Immune Immune Evasion Immune response Immune system Immunity Immunologic Stimulation Immunosuppression Impairment In Vitro Infiltration Knowledge Lymphocytic Infiltrate Malignant Neoplasms Malignant neoplasm of ovary Mediating Membrane Microglia Microsatellite Repeats Modality Modeling Morphology Mus Myeloid Cells Neoplasms Patients Peptide Hydrolases Phenotype Property Proteins Radiation therapy Recurrence Recurrent tumor Reporting Research Resistance Role Serine Serine Protease Signal Transduction Solid Neoplasm Sorting Stimulus Stromal Cells Surface T-Lymphocyte Testing Transforming Growth Factor beta Treatment Efficacy Tumor Escape Tumor Immunity Urothelium VEGFA gene Work anti-PD-1 cancer therapy cell type cytotoxic effective therapy fibroblast activation protein alpha immune cell infiltrate immune resistance immunogenic immunogenicity improved in vivo innovation irradiation malignant breast neoplasm member mouse model novel novel strategies novel therapeutic intervention pharmacologic pre-clinical prevent programmed cell death ligand 1 programmed cell death protein 1 recruit resistance mechanism single-cell RNA sequencing standard of care synergism temozolomide tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor disease with a median overall survival of approximately 15 months. GBM patients die because of the constant ability of GBM to acquire resistance mechanisms against anti-cancer therapies, therefore leading to an inevitable tumor recurrence. A. Radiation therapy (RT) is a pivotal modality for improving overall survival of GBM. However, GBM invar- iably recurs, which suggests that RT is eliciting or exacerbating mechanisms of resistance in GBM. Identifying and overcoming the contributing factors involved in GBM resistance is a major challenge. Immunosup- pression exerted by cells expressing fibroblast activating protein-alpha (FAP) can account for the lack of immu- nogenicity of irradiated GBM. FAP is a type II transmembrane serine protease that is heavily expressed in the stroma of multiple solid tumors and has thus become a marker to identify cancer-cell associated fibroblasts (CAFs). While our knowledge about CAFs or CAF-like cells in GBM is limited. Few studies reported the presence of glioblastoma-associated stromal cells (GASCs) that share phenotypic and functional properties of CAFs de- scribed in the stroma of carcinomas, but none investigated the role of this cell type in respect to immunosup- pression of irradiated GBM. Our preliminary analyses suggest that FAP+ cells represent a major immune sup- pressive subset in irradiated GBM. Specifically, we demonstrate that (1) FAP+ cells with fibroblastic morphology surround GBM tumor, (2) FAP is mostly expressed by tumor infiltrating myeloid cells in vivo, (3) in vitro irradiation of GBM and microglia cells enhances FAP together with PD-L1 and PD-L2 expressions and (4) targeting FAP increases the recruitment of CD8+ T cells and CD11c+ into GBM in vivo. This work shed light on FAP+ cells as a master regulator of anti- immunity and identifies FAP targeting as a new strategy to immune reactivity of irra- diated GBM. In this application, we propose to test the novel and innovative hypothesis that FAP+ cells represent a major immune suppressive subset that provide the means to suppress anti-tumor immunity in GBM. Successful completion of this work will (1) uncover the role of FAP+ cells in immunosuppression of irradiated GBM and (2) provide evidence for a novel therapeutic intervention that will break through immune resistance of irradiated GBM by targeting FAP.

项目摘要胶质母细胞瘤（GBM）是一种毁灭性的脑肿瘤疾病，总体存活率约为15 月份。 GBM患者死亡，因为GBM无法获得抵抗机制的能力抗癌疗法，因此导致不可避免的肿瘤复发。 A.辐射疗法（RT）是改善GBM总体存活的关键方式。但是，GBM不变相当复发，这表明RT在GBM中引起或加剧了抗性的机制。识别克服GBM抗性涉及的因素是一个主要挑战。免疫表达成纤维细胞激活蛋白α（FAP）的细胞所发挥的压力可以解释缺乏辐照GBM的诺原性。 FAP是II型跨膜丝氨酸蛋白酶，在多个实体瘤的基质，因此已成为鉴定癌细胞相关成纤维细胞的标志物（CAFS）。尽管我们对GBM中CAF或类似CAF的细胞的了解是有限的。很少有研究报告存在胶质母细胞瘤相关的基质细胞（GASC），它们具有CAFS的表型和功能特性在癌的基质中被涂抹，但没有人研究这种细胞类型在免疫术中的作用辐照GBM的压力。我们的初步分析表明，FAP+细胞代表了主要的免疫SUP- 辐照GBM中的压力子集。具体而言，我们证明了（1）具有成纤维细胞形态的FAP+细胞环绕GBM肿瘤，（2）FAP主要通过肿瘤浸润髓样细胞体内表达，（3）体外照射 GBM和小胶质细胞与PD-L1和PD-L2表达式以及（4）靶向FAP增强了FAP 将CD8+ T细胞和CD11C+募集到体内GBM中。这项工作将FAP+细胞阐明为抗免疫力的主要调节剂，并将FAP靶向鉴定为IRRA-免疫反应性的新策略 gbm。在此应用中，我们建议测试FAP+细胞的新颖和创新假设代表一个主要的免疫抑制子集，该子集提供了抑制抗肿瘤免疫力的手段 GBM。成功完成这项工作将（1）揭示FAP+细胞在免疫抑制中的作用受辐照的GBM和（2）提供了一种新型治疗干预的证据，该干预将突破通过靶向FAP，受辐照的GBM的免疫抵抗力。