Single Cell Methods for Bioeffector Discovery and Analysis

用于生物效应器发现和分析的单细胞方法

• 批准号: 10545185
• 负责人: BRIAN O BACHMANN
• 金额: $ 57.62万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-18 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545185
• 关键词: Acceleration; Actinobacteria class; Acute Myelocytic Leukemia; Address; Affect; Antigens; Antineoplastic Agents; Bacteria; Benchmarking; Biological Assay; Biology; Biopsy; Cancer Biology; Cancerous; Cell Death; Cell Death Induction; Cells; Chemicals; Chromatography; Classification; Clinical; Complex; Complex Mixtures; Computer software; Cytometry; Data Set; Diagnostic; Disease; Ecosystem; Environment; Evaluation; Evolution; Excision; Experimental Designs; Family; Health; Human; Immune; Immune Evasion; Immune response; Immune system; Immunoassay; Immunologic Surveillance; Immunooncology; Immunotherapeutic agent; Immunotherapy; Impairment; In Vitro; Individual; Investigation; Lead; Malignant - descriptor; Malignant Neoplasms; Measures; Methodology; Methods; Molecular; Molecular Profiling; Multidimensional NMR Techniques; Myxococcales; Natural Products; Nature; Non-Malignant; Patients; Pattern; Population; Primary Neoplasm; Process; Remission Induction; Repression; Research; Resolution; Sampling; Scientist; Signal Pathway; Signal Transduction; Source; Stromal Cells; Structure; System; Systems Analysis; T-Lymphocyte; Therapeutic Intervention; Tissue Sample; Tissues; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Work; adaptive immune response; anti-cancer; cancer cell; cancer therapy; cancer type; carcinogenesis; cell preparation; cell type; cheminformatics; chemotherapy; cytotoxic; high dimensionality; immune activation; immune checkpoint blockade; immunogenic cell death; immunogenicity; insight; interest; metabolome; metabolomics; microbial; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; patient response; patient subsets; precision medicine; recruit; response; secondary metabolite; small molecule; translational applications; translational potential; tumor; tumor microenvironment

PROJECT SUMMARY It is becoming increasingly apparent that discovering new therapeutics for the treatment of cancer must involve a consideration of: (A) The interplay between the host immune system and tumors. Cancer cells often have adapted the ability to evade immune surveillance, either by muted antigenicity or via actively disarming immune activation via immune checkpoint blockade. (B) The connection between chemotherapeutic interventions and immunogenicity. It has become apparent that the efficacy of many traditional chemotherapies is dependent upon enhancing the immunogenicity of cancer cells. Without a functional immune system, cytotoxic small molecules demonstrate decrease selectivity for cancer cells versus healthy ones. (C) The highly heterogeneous nature of tumors in their native environments. Tumors are comprised of a complex mixture of multiple tumor lineages embedded host tissue microenvironments. The structure and complexity of the tumor microenvironment has a direct bearing on the efficacy of therapeutic interventions. This proposal develops a new methodology for natural product discovery using biopsied human tumors and tumor infiltrating immune cells. Multiplexed activity metabolomics (MAM) merges flow cytometric microtiter well and bioassay multiplexing with metabolomics and cheminformatics software to radically accelerate bioactive compound discovery, and specifically addresses the above considerations in the context of the discovery of acute myeloid leukemia anticancer lead discovery. Additionally, experimental designs will provide new insights into the effect and mechanism of a reference set of known synthetic and natural small molecules, providing a basis set of cellular responses to cytotoxic small molecules for the evaluation of lead compounds generated during discovery efforts. Specific aims of this proposal are organized independently to develop a multiplexing system for bioeffector discovery, a multiplexing system for analysis of heterogeneous cell mixtures, and a deep cell response profiling via multiplexed immunoassay of markers of cell status. Aims circumscribe this plan for our cross-disciplinary team employing metabolomics, natural product chemical biology, and discovery (Bachmann), cytometry and cancer biology (Irish), and clinical cancer biology (Ferrell). We aim to: (1) Identify microbial metabolites that specifically target human cancer cells from primary tumor tissue samples to modulate anti-tumor immunity. (2) Discover metabolites that remodel immune cell population fates to enhance anti-tumor immunity, (3) Determine deep single cell metabolite responses of malignant and tumor-associated immune cells using known, clinically active molecules as reference points Relevance: This successful completion of the proposed research is highly relevant to human health because it will provide methods to accelerate the identification of potential anticancer natural products, which have had and continue to have a large impact on human health. Furthermore, the discovery of the multi-cell targeting immuno-oncological activity of known compound families, and newly discovered compounds may provide new targeted therapeutics, with greater efficiency and reduced clinical toxicity.

项目摘要 越来越明显的是，发现新的治疗癌症必须涉及 考虑：（a）宿主免疫系统与肿瘤之间的相互作用。癌细胞经常有 通过静音抗原性或通过主动解除免疫力来避免免疫监测的能力 通过免疫检查点封锁激活。 （b）化学治疗干预措施与 免疫原性。显然，许多传统化学疗法的功效取决于 增强癌细胞的免疫原性。没有功能性免疫系统，细胞毒性小分子 证明癌细胞与健康细胞的选择性降低。 （c）高度异构性的性质 肿瘤在其本地环境中。肿瘤由多个肿瘤谱系的复杂混合物组成 嵌入的宿主组织微环境。肿瘤微环境的结构和复杂性具有 直接取决于治疗干预的功效。该建议开发了一种新方法 使用活检的人类肿瘤和肿瘤浸润的免疫细胞发现天然产物。多路复用 活性代谢组学（MAM）合并流式细胞量微量滴定和生物测定的多重代谢组学 和化学信息学软件从根本上加速生物活性化合物发现，并专门解决 在发现急性髓样白血病抗癌铅发现的背景下的上述考虑。 此外，实验设计将为参考集的效果和机制提供新的见解 已知的合成和天然小分子，为细胞毒性小的基础提供了一组细胞反应 用于评估发现过程中产生的铅化合物的分子。该提议的具体目的 独立组织以开发用于生物效应器发现的多路复用系统，这是一个多路复用系统 用于分析异质细胞混合物，以及通过多重免疫测定的深层细胞反应分析 细胞状态的标记。 Aims限制了我们的跨学科团队采用代谢组学的跨学科团队， 天然产品化学生物学和发现（Bachmann），细胞术和癌症生物学（爱尔兰）和临床 癌症生物学（Ferrell）。我们的目标是：（1）确定特异性针对人类癌细胞的微生物代谢产物 从原发性肿瘤组织样品调节抗肿瘤免疫。 （2）发现重塑的代谢产物 免疫细胞种群命运以增强抗肿瘤免疫力，（3）确定深单细胞代谢物 使用已知的临床活性分子作为参考，恶性和肿瘤相关细胞的反应 积分相关性：拟议研究的成功完成与人类健康高度相关 因为它将提供加速潜在抗癌天然产品的方法，这 已经并继续对人类健康产生重大影响。此外，发现多细胞 靶向已知化合物家族的免疫肿瘤活动，以及新发现的化合物可能 提供新的靶向疗法，具有更高的效率和临床毒性降低。

项目成果

Circulating Myeloid Regulatory Cells: Promising Biomarkers in B-Cell Lymphomas.

• DOI: 10.3389/fimmu.2020.623993
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Ferrant J;Lhomme F;Le Gallou S;Irish JM;Roussel M
• 通讯作者: Roussel M

Nonclassical Monocytes Are Prone to Migrate Into Tumor in Diffuse Large B-Cell Lymphoma.

• DOI: 10.3389/fimmu.2021.755623
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Le Gallou S;Lhomme F;Irish JM;Mingam A;Pangault C;Monvoisin C;Ferrant J;Azzaoui I;Rossille D;Bouabdallah K;Damaj G;Cartron G;Godmer P;Le Gouill S;Casasnovas RO;Molina TJ;Houot R;Lamy T;Tarte K;Fest T;Roussel M
• 通讯作者: Roussel M

High-Dimensional Data Analysis Algorithms Yield Comparable Results for Mass Cytometry and Spectral Flow Cytometry Data.

• DOI: 10.1002/cyto.a.24016
• 发表时间: 2020-08
• 期刊: Cytometry. Part A : the journal of the International Society for Analytical Cytology
• 作者: Ferrer-Font L;Mayer JU;Old S;Hermans IF;Irish J;Price KM
• 通讯作者: Price KM

Picturing Polarized Myeloid Phagocytes and Regulatory Cells by Mass Cytometry.

通过质谱流式细胞仪描绘极化的骨髓吞噬细胞和调节细胞。

• DOI: 10.1007/978-1-4939-9454-0_14
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Roussel,Mikael;Bartkowiak,Todd;Irish,JonathanM
• 通讯作者: Irish,JonathanM

Mechanism of CD79A and CD79B Support for IgM+ B Cell Fitness through B Cell Receptor Surface Expression.

• DOI: 10.4049/jimmunol.2200144
• 发表时间: 2022-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Huse K;Bai B;Hilden VI;Bollum LK;Våtsveen TK;Munthe LA;Smeland EB;Irish JM;Wälchli S;Myklebust JH
• 通讯作者: Myklebust JH