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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：