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Regulation of the Tumor Immune Cell Landscape by Ciliated Glioblastoma Cells

纤毛胶质母细胞瘤细胞对肿瘤免疫细胞景观的调节

基本信息

批准号：
10641092
负责人：
Matthew Robert Sarkisian
金额：
$ 22.88万
依托单位：
UNIVERSITY OF FLORIDA
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：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641092
关键词：
Adult Affect Animal Model Biopsy Bone Marrow Brain Neoplasms Cell Communication Cell physiology Cells Centrioles Cilia Complex Coupled Cues Data Distal Electron Microscopy G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genes Glioblastoma Glioma Growth Histologic Human Immune Immune Targeting Immune system Immunity Immunophenotyping Immunotherapeutic agent Immunotherapy In Situ In Vitro Infiltration Interferon Type II Intracranial Neoplasms Ligands Macrophage Malignant neoplasm of brain Mediating Microglia Microtubules Mitosis Molecular Mothers Mus Myeloid-derived suppressor cells Nature Operative Surgical Procedures Organelles Outcome Patients Phenotype Poly A Positioning Attribute Primary Brain Neoplasms Process Production Proteins Radiation Recurrence Regulation Reporter Reporting Resistance SHH gene Sensory Signal Pathway Signal Transduction Specimen T-Cell Activation T-Lymphocyte Time Transcript Tumor Promotion Tumor Tissue Tumor-infiltrating immune cells anti-tumor immune response cancer cell cancer infiltrating T cells cell type chemotherapy cilium biogenesis cytotoxic digital effector T cell human disease in vivo irradiation monocyte mouse model neoplastic cell novel novel strategies prevent recruit response single-cell RNA sequencing standard of care temozolomide transcription factor transmission process tumor tumor diagnosis tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis

项目摘要

Project Summary Glioblastoma (GBM) is the most common and lethal form of brain cancer in adult, typically recurring after all therapies including surgery, chemotherapy, and radiation. A major part of the problem is that GBMs employ various mechanisms to suppress the host immune system, preventing the immune cells (e.g., cytotoxic effector T cells) from destroying and removing cancer cells. It is believed that tumor cells release or signal suppressive factors. Thus, a better understanding of the cellular and molecular crosstalk mechanisms between tumor and immune cell types are needed to advance immunotherapeutic approaches against brain tumors. Notably, we and others have reported that standard of care chemotherapy stimulates formation of primary cilia, an organelle that is likened to both a cellular ‘antenna’ and transmitter. The presence of cilia predicts more aggressive and treatment resistant GBM. We now show for the first time, in patient biopsies, that glioma- associated immune cells extend processes that contact the tumor cilia and cilia tip, thus positioned to send signals to or receive signals from GBM cells. Similar observations were made in intracranial GBM-bearing mice where we detected juxtaposition of cilia with recruited immune cells. Notably, cilia disproportionately and predominately associated with monocytic-MDSCs (M-MDSCs), a cell type with known T cell suppressive activity. In contrast, T cells rarely juxtaposed tumor cilia and maintained greater distances away from ciliated tumor cells compared to M-MDSCs. Our compelling data suggest potential mechanisms of crosstalk between ciliated tumor cells and specific immune-suppressive cell types that promote tumor progression and therapy resistance. Our working hypothesis is that GBM cilia are venues for mediating interactions with M-MDSCs, and this interaction supports their T cell suppressive activity. The aims of our studies will determine 1) how GBM cilia affect M-MDSC and T cell tumor infiltration and function, and 2) which immune cell types contact or avoid ciliated tumor cells in human GBM. We will tackle these aims by immunophenotyping syngeneic murine gliomas with or without cilia, and compare these findings to spatial profiling of the immune microenvironment around ciliated tumor cells in GBM patient specimens. Successful outcomes will shed light on a novel cell-cell interaction in the brain tumor microenvironment that may explain, in part, how tumor cells evade targeting by the immune system.

项目摘要胶质母细胞瘤（GBM）是成人中最常见和致命的脑癌，通常会复发治疗包括手术、化疗和放疗。问题的一个主要部分是，GBM雇用抑制宿主免疫系统，阻止免疫细胞（例如，细胞毒性效应 T细胞）破坏和清除癌细胞。据信肿瘤细胞释放或信号抑制因素因此，更好地理解肿瘤和肿瘤细胞之间的细胞和分子串扰机制，需要免疫细胞类型来推进针对脑肿瘤的免疫方法。值得注意的是，和其他人已经报道，标准护理化疗刺激初级纤毛的形成，一种细胞器，被比作细胞的“天线”和发射器。纤毛的存在预示着侵袭性和治疗抗性GBM。我们现在第一次在病人的活检中发现，神经胶质瘤- 相关的免疫细胞延伸接触肿瘤纤毛和纤毛尖端的过程，从而定位发送向GBM细胞发送信号或从GBM细胞接收信号。在颅内携带GBM的小鼠中也进行了类似的观察在那里我们检测到纤毛与募集的免疫细胞并置。值得注意的是，纤毛不成比例，主要与单核细胞-MDSC（M-MDSC）相关，M-MDSC是一种已知具有T细胞抑制作用的细胞类型，活动相比之下，T细胞很少与肿瘤纤毛并列，并且与纤毛细胞保持更大的距离。肿瘤细胞与M-MDSC相比。我们令人信服的数据表明，纤毛肿瘤细胞和促进肿瘤进展和治疗的特异性免疫抑制细胞类型阻力我们的工作假设是GBM纤毛是介导与M-MDSC相互作用的场所，并且这种相互作用支持它们的T细胞抑制活性。我们研究的目的将决定1）如何 GBM纤毛影响M-MDSC和T细胞肿瘤浸润和功能，以及2）哪些免疫细胞类型接触或避免人类GBM中的纤毛肿瘤细胞。我们将通过对同源小鼠进行免疫表型分析来解决这些问题。有或没有纤毛的胶质瘤，并将这些发现与免疫微环境的空间分布进行比较 GBM患者标本中纤毛肿瘤细胞周围。成功的结果将揭示一种新的细胞-细胞脑肿瘤微环境中的相互作用，这可能部分解释了肿瘤细胞如何通过免疫系统.