Understanding the role of β2AR-signaling on ILC2 differentiation/plasticity and its implications in cancer progression

了解 β2AR 信号传导对 ILC2 分化/可塑性的作用及其对癌症进展的影响

基本信息

批准号：
10750348
负责人：
Jee Eun Choi
金额：
$ 3.25万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750348
关键词：
Adrenergic Agents Adrenergic Receptor Adrenergic beta-Agonists Affect Antitumor Response Ants Binding Breast Cancer Model Cancer Biology Cancer Patient Cancer Prognosis Cell Differentiation process Cells Chronic stress Common Lymphoid Progenitor Cytotoxic T-Lymphocytes Data Development EO771 Ensure Enzyme-Linked Immunosorbent Assay Event Exhibits Fellowship Flow Cytometry GATA3 gene Goals Helper-Inducer T-Lymphocyte Immune Immune response Immunity Immunosuppression Immunotherapy In Vitro Infiltration Isoproterenol Knock-out Knockout Mice Knowledge Literature Lymphoid Cell Lymphoid Tissue Malignant Neoplasms Mediating Methodology Methods Molecular Moon Mus Myeloid-derived suppressor cells Natural Killer Cells Nature Nerve Norepinephrine Pathway Analysis Pathway interactions Patients Phenotype Physicians Play Population Pre-Clinical Model Proteins Publishing Receptor Signaling Regulation Role Scientist Signal Transduction Site Sorting Stress Surface T cell differentiation T-Lymphocyte Techniques Testing Training Treatment outcome Tumor Immunity Tumor Promotion Tumor Volume Work adrenergic stress anti-tumor immune response beta-2 Adrenergic Receptors breast cancer progression catalyst comparison control conditional knockout cytotoxic experience improved improved outcome in vivo Model melanoma nerve supply novel patient prognosis prevent response single-cell RNA sequencing skills tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Project Summary / Abstract: In preclinical models, norepinephrine released by sympathetic nerves during chronic stress have been demonstrated to promote an immunosuppressive tumor microenvironment (TME) through activation of the β2- adrenergic receptor (β2AR) on various cells including immune cells. This sequence of events could be detrimental to the treatment outcome in cancer patients who are experiencing increased levels of stress. Innate lymphoid cells (ILCs), specifically type II ILCs (ILC2s), have been demonstrated as a small but critical cell population within the TME. However, there is little known about the mechanisms that regulate ILC plasticity and function in the TME. Even though ILC2s express high levels of β2AR, how stress impacts ILC2 activity within the TME is not yet known. In new preliminary data, we have observed a correlation between increased ILC2s and decreased tumor volume in knock out mice lacking the β2AR. Furthermore, our data suggests a shift in ILC2 plasticity toward an anti-tumor phenotype upon loss of β2AR signaling by single-cell RNA sequencing. Therefore, we hypothesize that β2AR signaling activated by chronic stress drives the immunosuppressive function of ILC2s, suppressing the anti-tumor immune response within the tumor microenvironment. We will interrogate the role β2AR signaling plays as a rheostat in ILC development and plasticity into the helper ILC subsets by the two aims proposed here. In Aim 1, we will determine the effect of β2AR signaling on common lymphoid progenitors (CLPs) differentiation into ILC2s and ILC2 plasticity. Utilizing in vitro cultures of wildtype and β2AR-/- CLPs and ILC2s with a β-AR agonist treatment, we will analyze the changes in ILC subset ratios due to β2AR signaling. We will also elucidate the molecular mechanism by which these changes occur using both targeted and high-throughput methodologies. In Aim 2, we will determine the impact of β2AR signaling on ILC2-mediated tumor progression using IL-5creβ2-ARfl/fl conditional knockout mice. The changes in the TME and tumor growth in mice with a conditional β2AR knock out in ILC2 will be analyzed using spectral flow cytometry. Overall, this project will utilize in vitro and in vivo models and other state-of-the-art techniques to understand how chronic stress through β2- AR signaling hampers effective ant-tumor immune response in tumor microenvironment.

项目摘要 /摘要：在临床前模型中，在慢性应激期间通过交感神经释放的去甲肾上腺素一直是被证明是通过激活β2-促进免疫抑制肿瘤微环境（TME）包括免疫细胞在内的各种细胞上的肾上腺素受体（β2AR）。一系列事件可能是在压力水平增加的癌症患者中的治疗结果有害。先天淋巴样细胞（ILC），特别是II型ILC（ILC2），已被证明是一个小但临界细胞 TME内的人口。但是，关于调节ILC可塑性的机制鲜为人知在TME中的功能。即使ILC2表达高水平的β2AR，压力如何影响ILC2活性 TME尚不清楚。在新的初步数据中，我们观察到ILC2和缺乏β2AR的小鼠敲除肿瘤体积减少。此外，我们的数据表明ILC2发生了变化单细胞RNA测序失去β2AR信号传导后，可塑性对抗肿瘤表型。所以，我们假设由慢性应激激活的β2AR信号传导驱动ILC2S的免疫抑制功能，抑制肿瘤微环境中的抗肿瘤免疫反应。我们将审问角色 β2AR信号传导在ILC发育和可塑性中扮演的变阻器，并通过两个目的向辅助ILC子集发挥作用在这里提议。在AIM 1中，我们将确定β2AR信号传导对普通淋巴祖细胞（CLP）的影响分化为ILC2和ILC2可塑性。利用野生型和β2AR的体外培养 - / - Clps和ILC2S 通过β-AR激动剂治疗，我们将分析由于β2AR信号传导引起的ILC子集比的变化。我们将还阐明了使用靶向和高通量发生这些变化的分子机制方法。在AIM 2中，我们将确定β2AR信号传导对ILC2介导的肿瘤进展的影响使用IL-5CREβ2-ARFL/FL条件敲除小鼠。小鼠TME和肿瘤生长的变化有条件的β2AR在ILC2中的敲除，将使用光谱流式细胞仪进行分析。总体而言，该项目将使用体外和体内模型以及其他最先进的技术，以了解如何通过β2-- AR信号助攻在肿瘤微环境中有效的抗肿瘤免疫响应。