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

• 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
• 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

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.

项目概要 胶质母细胞瘤 (GBM) 是一种毁灭性的脑肿瘤疾病，中位总生存期约为 15 几个月。 GBM 患者因 GBM 持续获得抵抗机制的能力而死亡 抗癌治疗，因此导致不可避免的肿瘤复发。 答：放射治疗 (RT) 是改善 GBM 总体生存率的关键方法。然而，GBM invar- 容易复发，这表明放疗正在引发或加剧 GBM 的耐药机制。识别 克服 GBM 耐药性的影响因素是一项重大挑战。免疫抑制- 表达成纤维细胞激活蛋白-α (FAP) 的细胞施加的压力可以解释免疫功能的缺乏。 辐照 GBM 的无原性。 FAP 是一种 II 型跨膜丝氨酸蛋白酶，在 多种实体瘤的基质，因此已成为识别癌细胞相关成纤维细胞的标志物 （CAF）。虽然我们对 GBM 中的 CAF 或 CAF 样细胞的了解有限。很少有研究报告其存在 胶质母细胞瘤相关基质细胞 (GASC) 具有 CAF 的表型和功能特性 刻在癌症的基质中，但没有人研究这种细胞类型在免疫抑制方面的作用。 受辐射 GBM 的压迫。我们的初步分析表明 FAP+ 细胞代表了主要的免疫支持 受辐射 GBM 中的压迫子集。具体来说，我们证明 (1) 具有成纤维细胞形态的 FAP+ 细胞 GBM肿瘤周围，（2）体内FAP主要由肿瘤浸润骨髓细胞表达，（3）体外照射 GBM 和小胶质细胞的 FAP 以及 PD-L1 和 PD-L2 表达一起增强，并且 (4) 靶向 FAP 增加体内 GBM 中 CD8+ T 细胞和 CD11c+ 的募集。这项工作揭示了 FAP+ 细胞作为 抗免疫的主要调节剂，并将 FAP 靶向确定为针对免疫反应性的新策略 糖尿病 GBM。在此应用中，我们建议测试 FAP+ 细胞这一新颖且创新的假设 代表一个主要的免疫抑制子集，提供了抑制抗肿瘤免疫的方法 GBM。这项工作的成功完成将（1）揭示FAP+细胞在免疫抑制中的作用 辐照 GBM 的研究，以及 (2) 为一种新的治疗干预措施提供证据，该干预措施将突破 通过靶向 FAP 来增强受辐射 GBM 的免疫抵抗力。