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

基本信息

批准号：
10442529
负责人：
Allon Moshe Klein
金额：
$ 52.14万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2018-07-18 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442529
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

项目摘要

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.

项目概要肿瘤微环境是多种免疫细胞类型的家园，但目前的免疫治疗方法主要集中于激活溶细胞 T 细胞。其他骨髓谱系细胞对抗癌症的潜力迄今为止，人们的探索还少得多。例如，我们对骨髓细胞的复杂性了解有限。由于细胞亚型不同，我们无法完全区分促肿瘤细胞和抑肿瘤细胞，而且我们缺乏有关可用于治疗的已定义骨髓细胞相关分子途径的信息。在这里，我们将使用尖端的、公正的单细胞分析来揭示未被重视的免疫调节骨髓细胞类型以及体外和体内扰动，揭示了未受重视的肿瘤浸润骨髓（TIM）细胞群并定义其在肺癌中的功能作用。为此，我们首先要确定人类 TIM 状态、它们与临床参数的相关性，以及这些状态之间是否保守人和小鼠肺腺癌。我们将专门测试以下假设：i) 尚未得到重视人类患者的肿瘤和外周血中的骨髓细胞状态与患者的生存相关（并且可能还有其他临床参数），以及 ii）基因工程小鼠肺肿瘤模型腺癌宿主保守的人类 TIM 状态并证明对这些功能的进一步动物研究是合理的州。其次，考虑到我们的初始数据，我们将重点关注所谓的 GN2 和 GN3 中性粒细胞子集显示它们在人类和小鼠肺部肿瘤中的存在及其与癌症进展的相关性（科学，2017 年出版，本申请中包含我们未发表的数据）并且中性粒细胞是正在成为多种实体瘤（尤其是肺癌）生存的强有力预测因子。我们将特别测试以下假设：i) GN2 和 GN3 中性粒细胞具有不同的肿瘤促进功能，并且 ii) 这些亚群使用特定的分子信号传导途径促进肺癌进展。为了实现我们的为了实现目标，我们将结合两个具有互补专业知识的实验室的努力：肿瘤免疫生物学和骨髓学细胞 (Pittet)、单细胞 RNA 测序 (scRNA-Seq) 和理论/生物信息学 (Klein)。我们还有进一步与临床医生合作，从肺癌患者身上获取血液样本和新鲜肿瘤活检（我们的初步数据也包含在本申请中）。总的来说，这里开发的方法和资源可能对开发新的、更有效的免疫疗法产生重大影响。此外，通过瞄准除了 T 细胞之外的免疫系统，我们将利用非冗余免疫成分的多样性作为一种方法克服当前治疗方案的局限性。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of a Tissue-Engineered Oral Mucosa Model to Investigate the Role of Tumour-Associated Macrophages in Oral Cancer Progression

开发组织工程口腔粘膜模型来研究肿瘤相关巨噬细胞在口腔癌进展中的作用

DOI：
10.1016/j.jcsr.2011.06.003
发表时间：
2017-04-01
期刊：
Journal of Constructional Steel Research
影响因子：
4.1
作者：
L. Hadley
通讯作者：
L. Hadley

Dendritic cells direct circadian anti-tumour immune responses.

树突状细胞指导昼夜节律抗肿瘤免疫反应。

DOI：
发表时间：
2023-02
期刊：
影响因子：
64.8
作者：
Wang, Chen;Barnoud, Coline;Cenerenti, Mara;Sun, Mengzhu;Caffa, Irene;Kizil, Burak;Bill, Ruben;Liu, Yuanlong;Pick, Robert;Garnier, Laure;Gkountidi, Olga A;Ince, Louise M;Holtkamp, Stephan;Fournier, Nadine;Michielin, Olivier;Speiser, Daniel E
通讯作者：
Speiser, Daniel E

A neutrophil response linked to tumor control in immunotherapy.

中性粒细胞反应与免疫治疗中的肿瘤控制有关。

DOI：
发表时间：
2023-03-30
期刊：
影响因子：
64.5
作者：
Gungabeesoon, Jeremy;Gort;Kiss, Máté;Bolli, Evangelia;Messemaker, Marius;Siwicki, Marie;Hicham, Mehdi;Bill, Ruben;Koch, Peter;Cianciaruso, Chiara;Duval, Florent;Pfirschke, Christina;Mazzola, Michael;Peters, Solange;Homicsk
通讯作者：
Homicsk