S100A4 mediated immune suppression in GBM

S100A4 介导 GBM 中的免疫抑制

• 批准号: 10556428
• 负责人: KYUSON YUN
• 金额: $ 43.87万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556428
• 关键词: Adult; Anti-Inflammatory Agents; Astrocytes; Biological Response Modifiers; Bone Marrow; Brain Neoplasms; Calcium-Binding Proteins; Cancer Patient; Cells; Cementation; Complement; Data; Data Analyses; Disease; Disease Progression; Environment; Glioblastoma; Glioma; Goals; Human; Immune; Immune Evasion; Immune System Diseases; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; Inflammatory; Interleukin-10; Laboratories; Leukocytes; Literature; Macrophage; Malignant Neoplasms; Malignant neoplasm of brain; Manuscripts; Mediating; Mediator; Mesenchymal; Microglia; Modality; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Penetration; Phenotype; Preparation; Radiation therapy; Recurrence; Regulation; Regulatory T-Lymphocyte; Reporting; Role; S100A4 gene; Signal Transduction; Solid Neoplasm; Stromal Cells; T cell infiltration; T-Lymphocyte; Testing; The Cancer Genome Atlas; Tissues; Visualization; Work; aggressive therapy; cancer cell; cancer type; chemokine; chemotherapy; cytokine; effector T cell; extracellular; genetic signature; immune cell infiltrate; immunoregulation; immunosuppressive macrophages; immunotherapy trials; in vivo imaging; insight; knock-down; molecular phenotype; molecular subtypes; monocyte; mouse model; multi-photon; novel; novel strategies; polarized cell; pre-clinical; programs; protein function; recruit; single cell sequencing; single-cell RNA sequencing; stem cell self renewal; success; trafficking; tumor; tumor-immune system interactions; virtual

Project Summary Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is virtually incurable. Despite aggressive treatments that include surgery, radiation therapy, and chemotherapy, the average survival is 15.4 months, with less than 5% of patients surviving > 5 years. Immunotherapy is a promising new approach to treat GBM as it harnesses one’s own immune system to recognize and kill aberrant cancer cells. Unfortunately, ongoing trials with immunotherapies show disappointing results in most GBM patients, indicating that we need to better understand the intricate and dynamic interactions between glioma and immune cells that generate and maintain highly immune suppressive microenvironment in GBM. The major goal of this application is to test our hypothesis that S100A4 is a critical regulator of the GBM immune landscape. S100A4 is a small calcium binding protein that functions intracellularly as well as extracellularly. We recently reported that S100A4 is necessary for human and mouse glioma stem cell self- renewal. Our single cell RNA-sequencing analyses of human GBM shows that S100A4 is expressed in both glioma cells and immune suppressive leukocytes. Consistently, TCGA data analyses indicate that S100A4 expression is strongly correlated with primary and recurrent GBM patient survival, the mesenchymal subtype, and immune-suppressive macrophage markers (such as CD163, CD206, and IL10). Importantly, our unpublished results show that S100A4 in human and mouse glioma cells regulates expression of chemokines and cytokines that control immune cell infiltration and polarization towards immune suppressive phenotypes. Notably, knocking down S100a4 in glioma cells is sufficient to reprogram the immune environment and allow dramatic increase in T-cell infiltration and activation in mouse gliomas. Furthermore, deletion of S100a4 in the host mouse is also sufficient to reprogram the glioma immune landscape and extend survival (manuscripts in preparation). Therefore, we hypothesize that S100A4 functions in both glioma and immune to promote immune-suppressive environment in GBM through multiple mechanisms. To test this hypothesis, we will: 1) elucidate mechanisms through which S100A4 expression in glioma cells promotes local immune-suppressive microenvironment in GBM (Aim 1); and 2) determine mechanisms through which S100a4 expression in immune cells controls myeloid and T cell trafficking, polarization, and function (Aim2). Successful completion of this study will reveal how S100A4 regulates glioma associated immune cell infiltration/polarization and identify a potential novel immunotherapy target to treat GBM.

项目摘要 胶质母细胞瘤(GBM)是成人中最常见和最具侵袭性的恶性脑肿瘤，几乎 不治之症。尽管积极的治疗包括手术、放射治疗和化疗，但平均 生存期为15.4个月，不到5%的患者存活5年。免疫疗法是一种很有前途的新疗法 治疗基底膜的方法，因为它利用自己的免疫系统来识别和杀死变异的癌细胞。 不幸的是，正在进行的免疫疗法试验在大多数GBM患者中显示令人失望的结果，表明 我们需要更好地了解胶质瘤和免疫细胞之间复杂而动态的相互作用 在GBM中产生和维持高度免疫抑制的微环境。 这个应用程序的主要目标是测试我们的假设，即S100A4是GBM的关键调节因子 免疫景观。S100A4是一种小的钙结合蛋白，它在细胞内以及 在细胞外。我们最近报道了S100A4是人和小鼠胶质瘤干细胞自身所必需的 更新。我们对人GBM进行的单细胞RNA测序分析表明，S100A4在这两种细胞中都有表达 胶质瘤细胞和免疫抑制白细胞。TCGA数据分析一致表明，S100A4 表达与原发和复发的GBM患者的生存期、间充质亚型、 和免疫抑制巨噬细胞标志物(如CD163、CD206和IL10)。重要的是，我们的 未发表的结果表明，S100A4在人和小鼠胶质瘤细胞中调节趋化因子的表达 以及控制免疫细胞向免疫抑制表型渗透和极化的细胞因子。 值得注意的是，击倒胶质瘤细胞中的S100a4足以重新编程免疫环境，并允许 小鼠脑胶质瘤中T细胞的侵袭和活化显著增加。此外，删除S100a4在 宿主小鼠也足以重新编程胶质瘤的免疫格局并延长生存期(手稿在 准备)。因此，我们假设S100A4在胶质瘤和免疫促进中都发挥作用 GBM中的免疫抑制环境通过多种机制。为了验证这一假设，我们将： 1)阐明S100A4在胶质瘤细胞中表达促进局部免疫抑制的机制 GBM中的微环境(目标1)；以及2)决定S100a4在免疫中表达的机制 细胞控制髓系和T细胞的运输、极化和功能(AIM2)。顺利完成这项研究 将揭示S100A4如何调节胶质瘤相关免疫细胞的渗透/极化，并确定潜在的 治疗基底膜的新免疫治疗靶点。