Single Cell Genome-Wide Myeloid Response Profiling in Immunotherapy

免疫治疗中的单细胞全基因组骨髓反应分析

• 批准号: 10183187
• 负责人: Allon Moshe Klein
• 金额: $ 53.77万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-18 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183187
• 关键词: Affect; Animals; Attention; Bioinformatics; Biological Assay; Biological Models; Biopsy; Blood specimen; CCL3 gene; Cancer Patient; Catalogs; Cell Lineage; Cell physiology; Cells; Clinical; Cytotoxic T-Lymphocytes; Data; Etiology; Flow Cytometry; Fostering; Genetically Engineered Mouse; Goals; Grant; Histology; Home; Human; Immune; Immune Targeting; Immune system; Immunobiology; Immunotherapeutic agent; Immunotherapy; In Vitro; Knowledge; Lung; Lung Adenocarcinoma; Lung Neoplasms; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Methods; Minority; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Pathway interactions; Patients; Play; Population; Property; Resources; Role; Sampling; Science; Signal Pathway; Solid Neoplasm; Structure; T-Lymphocyte; Testing; Time; Tissue Microarray; Tumor Tissue; cancer therapy; cell type; cost; fighting; genome-wide; granulocyte; human disease; immunoregulation; in vivo; mouse model; neutrophil; novel; novel therapeutics; peripheral blood; response; single-cell RNA sequencing; survival prediction; theories; therapeutic target; tumor; tumor heterogeneity; tumor microenvironment; tumor progression

Project summary Tumor microenvironments are home to diverse immune cell types but current immunotherapeutic approaches are focused largely on activating cytolytic T cells. The potential of other, myeloid lineage cells in fighting cancer are hitherto much less explored. For example, we have a limited understanding of the complexity of myeloid cell subtypes, we cannot fully discriminate between tumor-promoting and tumor-suppressing cells, and we lack information about defined myeloid cell-associated molecular pathways that could be harnessed for therapy. Here, we will use cutting-edge, unbiased single cell profiling to reveal unappreciated immunoregulatory myeloid cell types, alongside in vitro and in vivo perturbations, to reveal unappreciated tumor-infiltrating myeloid (TIM) cell populations and define their functional role in lung cancer. To this end, we will first determine human TIM states, their correlation with clinical parameters, and whether these states are conserved between human and mouse lung adenocarcinoma. We will specifically test the hypotheses that i) yet-unappreciated myeloid cell states in tumors and peripheral blood of human patients correlate with patient survival (and possibly other clinical parameters), and ii) genetically engineered mouse tumor models of lung adenocarcinoma host conserved human TIM states and justify further animal studies of the function of these states. Second, we will focus on so-called GN2 and GN3 neutrophil subsets, considering our initial data showing their existence in both human and mouse lung tumors and their relevance to cancer progression (Science, 2017 in Press and our unpublished data included in this application) and that neutrophils are emerging as strong predictors of survival for diverse solid tumors and most notably lung cancer. We will specifically test the hypotheses that i) GN2 and GN3 neutrophils have distinct tumor-promoting functions, and ii) these subsets use specific molecular signaling pathways to foster lung cancer progression. To achieve our goals, we will combine efforts of two labs with complementary expertise: tumor immunobiology and myeloid cells (Pittet), and single cell RNA sequencing (scRNA-Seq) and theory/bioinformatics (Klein). We have further teamed up with clinicians to obtain both blood samples and fresh tumor biopsies from lung cancer patients (our preliminary data are also included in this application). Overall, the approaches and resources developed here could have major implications for developing new and more efficient immunotherapies. Also, by targeting the immune system beyond T cells, we will exploit the diversity of non-redundant immune components as a way to overcome limitations of current treatment options.

项目摘要 肿瘤微环境是各种免疫细胞类型的家园，但当前的免疫治疗方法 主要集中在激活细胞溶解细胞上。其他粒细胞细胞在抗癌中的潜力 迄今为止的探索要少得多。例如，我们对髓样的复杂性有限 细胞亚型，我们不能完全区分肿瘤促进和肿瘤抑制细胞，我们缺乏 有关定义的髓样细胞相关分子途径的信息，这些途径可以利用进行治疗。 在这里，我们将使用尖端的，公正的单细胞分析来揭示未欣赏的免疫调节性 髓样细胞类型，以及体外和体内扰动，以揭示不受欢迎的肿瘤浸润 髓样（TIM）细胞群，并定义其在肺癌中的功能作用。为此，我们将首先确定 人类蒂姆国家，它们与临床参数的相关性，以及这些状态是否在 人和小鼠肺腺癌。我们将专门检验i）尚未认可的假设 肿瘤中的髓样细胞态和人类患者的外周血与患者的生存相关（和 可能是其他临床参数）和ii）肺的基因工程小鼠肿瘤模型 腺癌宿主保守的人类tim状态，并证明了进一步的动物研究这些功能 国家。其次，我们将重点关注所谓的GN2和GN3中性粒细胞子集，考虑到我们 显示它们在人和小鼠肺肿瘤中的存在及其与癌症进展的相关性 （科学，2017年的新闻和我们未发表的数据），中性粒细胞是 作为多种实体瘤和最著名的肺癌生存的强大预测指标。我们将 特别测试了i）i）gn2和gn3中性粒细胞具有独特的肿瘤功能，并且 ii）这些子集使用特定的分子信号通路来促进肺癌的进展。实现我们的 目标，我们将将两个实验室的努力与互补的专业知识相结合：肿瘤免疫生物学和髓样 细胞（Pittet）和单细胞RNA测序（SCRNA-SEQ）和理论/生物信息学（Klein）。我们还有更多 与临床医生合作，从肺癌患者那里获得血液样本和新鲜的肿瘤活检（我们的 初步数据也包含在此应用程序中）。总体而言，这里开发的方法和资源 可能对开发新的，更有效的免疫疗法具有重大影响。另外，通过针对 除T细胞以外的免疫系统，我们将利用非冗余免疫成分的多样性作为一种方式 克服当前治疗选择的局限性。