Macrophage phenotype polarization in clinical neoplasia

临床肿瘤中巨噬细胞表型极化

• 批准号: 10183194
• 负责人: Robert B West
• 金额: $ 55.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183194
• 关键词: Area; B-Lymphocyte Subsets; Bioinformatics; Biological; Biological Markers; Biology; Blood Vessels; Carcinoma; Cells; Clinical; Colon Carcinoma; Colorectal Cancer; Complex; Data; Development; Epithelial; Fibroblasts; Formalin; Gene Expression; Gene Expression Profiling; Genes; Geographic Locations; Histologic; Human; Imaging Techniques; Immune; In Vitro; Individual; Inflammatory; Liquid substance; Location; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Microscopic; Modeling; Molecular; Multiplexed Ion Beam Imaging; Mus; Neoplasms; Outcome; Paraffin Embedding; Patients; Phenotype; Physiological; Physiology; Prognosis; Research; Resolution; Sampling; Scientist; Specimen; Stains; T-Lymphocyte; Technology; Tissues; Tumor stage; Tumor-infiltrating immune cells; Validation; base; cancer type; cell type; density; experimental study; imaging biomarker; in silico; in vivo; insight; laser capture microdissection; macrophage; malignant breast neoplasm; monocyte; mouse model; new technology; novel; novel marker; novel strategies; synergism; targeted treatment; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT Macrophages constitute a major subset of cells in the cancer tumor microenvironment (TME), but despite decades of research in murine models and in vitro studies on human blood monocyte-derived macrophages there are no reliable markers to detect the various macrophage functions in the human TME and no systematic study on human macrophage in vivo functional diversity has been performed. Current understanding of macrophage biology is based on findings from murine studies and ex vivo experiments on human blood monocyte-derived macrophages but these have not translated well into human tumor physiology. A convergence of three novel technologies (Smart-3SEQ, CIBERSORTx and MIBI) now offers an opportunity to discover novel markers by studying macrophages in vivo at the microscopic level in the actual TME rather than in a model thereof. We hypothesize that those studies do not represent the true physiological state in vivo because they lack the complex context of the human TME. New technologies will enable us to discover subtypes/phenotypes associated with different functions by directly studying human tumor samples where macrophages are known to have different activities. Our proposal represents an entirely novel approach to study TAM by comparing them in the setting of two distinct carcinomas, breast cancer and colon cancer; two tumor types in which TAM fulfill opposing functions. We will also analyze TAM at the microscopic level within distinct regions of the TME, thus identifying genes that distinguish distinct macrophage subsets based on their location within tissue. Finally, we will study changes in their expression profiles during different stages of tumor progression. This project will provide fundamental new biological insights into the diversity of macrophages in the context of human cancer. It will provide new biomarkers that can be used to provide a rational decision for the choice of novel macrophage- targeting therapy.

项目总结/摘要 巨噬细胞构成癌症肿瘤微环境（TME）中的主要细胞亚群，但尽管如此， 数十年的小鼠模型研究和人血单核细胞源性巨噬细胞体外研究 没有可靠的标记物来检测人TME中的各种巨噬细胞功能， 对人巨噬细胞在体内功能多样性进行了研究。目前了解的 巨噬细胞生物学是基于来自小鼠研究和对人血液的离体实验的发现 单核细胞衍生的巨噬细胞，但这些还没有很好地转化为人类肿瘤生理学。一 三种新技术（Smart-3SEQ、CIBERSORTx和MIBI）的融合现在提供了一个机会， 通过在实际TME中在微观水平上研究体内巨噬细胞来发现新的标志物，而不是 在其模型中。 我们假设这些研究并不能代表真实的体内生理状态，因为它们缺乏 人类TME的复杂背景。新技术将使我们能够发现亚型/表型 通过直接研究已知巨噬细胞的人类肿瘤样本， 有不同的活动。 我们的建议代表了一个全新的方法来研究TAM，通过比较他们在两个 不同的癌症，乳腺癌和结肠癌; TAM履行相反功能的两种肿瘤类型。 我们还将在TME的不同区域内分析微观水平的TAM，从而识别基因 根据它们在组织中的位置区分不同的巨噬细胞亚群。最后，我们将研究 在肿瘤进展的不同阶段其表达谱的变化。本项目将提供 对人类癌症背景下巨噬细胞多样性的基本新生物学见解。它将 提供了新的生物标志物，可用于为选择新的巨噬细胞提供合理的决定， 靶向治疗