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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结越来越明显的是，发现治疗癌症的新疗法必须包括考虑：(A)宿主免疫系统和肿瘤之间的相互作用。癌细胞通常有适应了通过抑制抗原性或主动解除免疫来逃避免疫监视的能力通过免疫检查点封锁激活。(B)化疗干预措施与免疫原性。很明显，许多传统化疗的疗效取决于增强癌细胞的免疫原性。如果没有功能正常的免疫系统，细胞毒性小分子与健康细胞相比，对癌细胞的选择性降低。(C)高度异质的性质原生环境中的肿瘤。肿瘤是由多种肿瘤谱系组成的复杂混合体。嵌入宿主组织微环境。肿瘤微环境的结构和复杂性直接关系到治疗干预的效果。这项建议开发了一种新的利用活组织检查的人类肿瘤和肿瘤浸润性免疫细胞发现的自然产物。多路传输活性代谢组学(MAM)很好地融合了流式细胞仪微量滴度和生物测定多重与代谢组学和化学信息学软件，从根本上加快生物活性化合物的发现，并具体解决以上考虑在发现急性髓系白血病的背景下率先发现抗癌药物。此外，实验设计将提供对参考集合的影响和机制的新见解已知的合成和天然小分子，为细胞对细胞毒性小分子的反应提供了一套基础用于评估在发现过程中产生的先导化合物的分子。这项提案的具体目标独立组织起来开发一种用于生物效应器发现的多路传输系统，一种多路传输系统用于异种细胞混合物的分析，以及通过多重免疫分析的深层细胞反应图谱细胞状态的标志物。旨在为我们利用代谢组学的跨学科团队制定这一计划，天然产物化学生物学和发现(巴赫曼)、细胞学和癌症生物学(爱尔兰)和临床癌症生物学(费雷尔)。我们的目标是：(1)识别针对人类癌细胞的微生物代谢物从原发肿瘤组织样本中提取，以调节抗肿瘤免疫。(2)发现重塑的代谢物免疫细胞群命运决定增强抗肿瘤免疫，(3)确定深层单细胞代谢物以已知临床活性分子为参照物的恶性肿瘤和肿瘤相关免疫细胞的反应要点相关性：这项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鉴定潜在抗癌天然产物的方法，已经并将继续对人类健康产生巨大影响。此外，多细胞的发现以已知化合物家族的免疫肿瘤活性为靶点，新发现的化合物可能提供新的靶向治疗，具有更高的效率和更低的临床毒性。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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。