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.

项目摘要 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 个月GBM患者死亡是因为GBM获得抵抗机制的恒定能力， 抗癌治疗，因此导致不可避免的肿瘤复发。 A.放射治疗（RT）是提高GBM总生存率的关键方法。然而，GBM因瓦- 这表明RT引发或加剧了GBM中的耐药机制。识别 并且克服涉及GBM抗性的促成因素是一个主要挑战。免疫抑制剂 由表达成纤维细胞活化蛋白-α（FAP）的细胞施加的表达可以解释免疫缺陷的缺乏。 照射GBM的致瘤性。FAP是一种II型跨膜丝氨酸蛋白酶，其大量表达于细胞膜中。 基质的多种实体瘤，并因此成为一种标志物，以确定癌细胞相关的成纤维细胞 （CAFs）。但我们对GBM中CAF或CAF样细胞的认识有限。很少有研究报道 胶质母细胞瘤相关的基质细胞（GASC），共享CAFs的表型和功能特性， 在癌的间质中转录，但没有人研究这种细胞类型在免疫抑制方面的作用。 照射GBM的压力。我们的初步分析表明，FAP+细胞是一种主要的免疫抑制剂， 受照射的GBM中的抑制亚群。具体而言，我们证明：（1）FAP+细胞具有成纤维细胞形态， FAP主要表达于肿瘤周围的骨髓细胞，（2）体内FAP主要表达于肿瘤浸润的骨髓细胞，（3）体外照射 GBM和小胶质细胞的表达增强FAP以及PD-L1和PD-L2的表达，以及（4）靶向FAP 增加体内CD 8 + T细胞和CD 11 c+向GBM的募集。这项工作揭示了FAP+细胞， 抗免疫的主要调节剂，并确定FAP靶向作为一种新的策略，免疫反应性的irra， 扩张性GBM。在本申请中，我们提出测试FAP+细胞 代表一个主要的免疫抑制亚群，其提供了抑制抗肿瘤免疫的手段， 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 和（2）为一种新的治疗干预提供证据， 通过靶向FAP的辐射GBM的免疫抗性。