Diversity Supplement Ifediora: Image-based models of tumor-immune dynamics in glioblastoma

多样性补充 Ifediora：胶质母细胞瘤肿瘤免疫动力学的基于图像的模型

• 批准号: 10746512
• 负责人: Peter Canoll
• 金额: $ 8.13万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746512
• 关键词: Advanced Malignant Neoplasm; Artificial Intelligence; Biology; Biopsy; Brain; Brain Neoplasms; Cell Communication; Cell Death Induction; Cells; Coculture Techniques; Computer Models; Disease; Early identification; Environment; Evolution; Genomics; Glioblastoma; Glioma; Image; Image Guided Biopsy; Immune; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Interest Group; Link; Macrophage; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Methods; Microglia; Modeling; Myelogenous; Neuroglia; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Research; Signal Transduction; System; Therapeutic; Topotecan; Treatment Protocols; Tumor Promotion; aggressive therapy; anticancer research; biological heterogeneity; cancer care; cancer cell; cell type; chemotherapy; immunogenic cell death; immunoreactivity; individual patient; non-invasive imaging; parent grant; radiomics; response; single-cell RNA sequencing; tumor; tumor heterogeneity; tumor microenvironment

Abstract Glioblastoma Multiforme (GBM) is the most common of all gliomas with a median survival 14-18 months, despite aggressive treatment regimens. However, glioma is a disease that encompasses more than just cancer cells. In fact, many studies have shown that glioma can alter the brain microenvironment in ways that promote tumor survival and propagation. Within this brain tumor microenvironment is a diversity of cell types. One of particular group of interest is glioma associated microglia and macrophages (GAMMs), an important component of the immune cells in the brain. As a result, immunotherapy is emerging as a promising method to treat cancer; however, we are not able to identify early response or predict who will respond. While biopsies are the most reliable way to assess the immunological landscape within the tumor, we are limited both spatially and temporally in the number of biopsies we can obtain, particularly for brain tumor patients. The heterogeneity of the tumor-immune landscape across patients suggests that a patient-specific approach will be required to accurately assess each patient’s individual tumor-immune environment and the evolution thereof. As part of the Parent Grant, we will use non-invasive imaging, image-guided biopsies, computational modeling, and artificial intelligence to bridge spatial and temporal scales and predict the abundance of glioma associated microglia/macrophages (GAMMs) comprising each magnetic resonance image (MRI) at the voxel level. Linking the MRI to the biological heterogeneity using radiomics approaches provides an opportunity to individualize our understanding of the tumor-immune environment. Also in recent years, research has looked into how drug treatment is able to activate GAMMs to take on immunoreactive phenotypes. For this proposed supplement we will characterize myeloid – glioma cell interactions in response to immunogenic cell death induced by the chemotherapy drug topotecan. This will be done using MRI localized biopsies as well as in vitro co-culture systems, providing an additional therapeutically relevant context in which to study cellular response and signaling. The study will make use of single cell RNA sequencing to identify activational states of immune cells, and will provide us with another aspect of microglia and macrophage biology that can be incorporated into the model generated in the Parent Grant.

抽象的 多形性胶质母细胞瘤 (GBM) 是所有胶质瘤中最常见的，中位生存期为 14-18 尽管采取了积极的治疗方案，但仍持续了数月。然而，神经胶质瘤是一种疾病 不仅仅包括癌细胞。事实上，许多研究表明神经胶质瘤可以 以促进肿瘤存活和增殖的方式改变大脑微环境。之内 这种脑肿瘤微环境是多种细胞类型的。特定利益群体之一 是神经胶质瘤相关的小胶质细胞和巨噬细胞（GAMM），是神经胶质瘤的重要组成部分 大脑中的免疫细胞。因此，免疫疗法正在成为一种有前途的方法 治疗癌症；然而，我们无法识别早期反应或预测谁会做出反应。 虽然活检是评估免疫学状况的最可靠方法 肿瘤，我们可以获得的活检数量在空间和时间上都受到限制， 特别是对于脑肿瘤患者。肿瘤免疫景观的异质性 患者建议需要采取针对患者的方法来准确评估每个患者的情况 患者的个体肿瘤免疫环境及其演变。作为家长的一部分 格兰特，我们将使用非侵入性成像、图像引导活检、计算模型和 人工智能连接时空尺度并预测神经胶质瘤的丰度 包含每个磁共振图像的相关小胶质细胞/巨噬细胞 (GAMM) （MRI）体素水平。使用放射组学将 MRI 与生物异质性联系起来 方法提供了一个机会来个性化我们对肿瘤免疫的理解 环境。近年来，研究还探讨了药物治疗如何能够 激活 GAMM 呈现免疫反应表型。对于这个拟议的补充，我们将 表征骨髓-神经胶质瘤细胞响应诱导的免疫原性细胞死亡的相互作用 通过化疗药物拓扑替康。这将通过 MRI 局部活检以及 体外共培养系统，提供了额外的治疗相关背景 研究细胞反应和信号传导。该研究将利用单细胞 RNA 测序来 识别免疫细胞的激活状态，将为我们提供小胶质细胞的另一个方面 和巨噬细胞生物学，可以纳入父母资助中生成的模型中。