Profiling immune cells in aged lung tumor initiation

分析老年肺肿瘤发生过程中的免疫细胞

基本信息

批准号：
10830688
负责人：
MARCIA HAIGIS
金额：
$ 17.18万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10830688
关键词：
ATAC-seq Age Aging Alveolar Alveolar Cell Atlases CD8-Positive T-Lymphocytes Cancer Etiology Cell physiology Cells Cessation of life Clinical Complex Data Defect Distal Epithelium Exhibits Flow Cytometry Future Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Genetically Engineered Mouse Goals Granzyme Homeostasis Immune Immune system Immunologic Surveillance Impairment Inflammatory Interferon Type II Interferons Joints Laboratories Lung Lung Adenocarcinoma Lung Neoplasms Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Mus Organoids Parents Population Predisposition Prevalence Process Proteins Regenerative capacity Risk Factors Role Shapes Signal Transduction TNF gene Tumor Immunity Tumor-infiltrating immune cells Up-Regulation Variant age related aged anti-tumor immune response cancer cell cell injury cell killing cell type cytokine cytotoxic draining lymph node immune function immunogenicity improved in vivo interest lung tumorigenesis mouse model neoplastic cell progenitor programs repaired response self-renewal single cell sequencing single-cell RNA sequencing stem cells tumor tumor growth tumor immunology tumor initiation tumor microenvironment tumorigenesis tumorigenic

项目摘要

Project Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-23-045. The immune system can control tumor growth and shape tumor immunogenicity through the process of cancer immunoediting, which results in the selection of tumor cell variants that can resist, avoid, or suppress the anti-tumor immune response and leads to outgrowth of clinically apparent tumors. Studying the impact of age on immunoediting in the cell type that gives rise to the most common type of lung cancer is critical to understanding the early stages of tumorigenesis. The predominant cell-of-origin in lung adenocarcinoma is the alveolar type 2 cells (AT2 cells), a progenitor cell population in the distal lung. In the first year of the parental U01 studies, we demonstrated that aged AT2 cells exhibit defects in self-renewal, exhibited by decreased organoid formation in culture and impaired ability to repair alveolar cell injury in vivo. We also established a genetically engineered mouse model (GEMM) of lung adenocarcinoma in young and aged mice and identified altered immune cell proportions and cytokines in aged vs. young tumors. In this supplement, we seek to uncover changes in immune cells in the aged milieu that may influence AT2 cell functions and define alterations in immune cells that may contribute to increased tumorigenesis during aging. We investigate these questions in two specific aims: Aim 1: To assess age-related gene regulation changes in lung lymphocytes and interacting lung epithelial progenitors. We will 1a) use multiparameter flow cytometry to determine age-related compositional changes of lung epithelium and immune cells and 1b) single cell sequencing to identify age-related differences in interactions between immune cells and lung epithelial progenitors at homeostasis. Aim 2: To define the changes in young vs. aged immune cell populations in the GEMM model of lung adenocarcinoma. We will 1a) define the immune cell populations altered by age in the TME vs. periphery using flow cytometry and 1b) dissect single cell transcriptional programs in immune cells from tumors from young vs. aged mice. This supplement will bring together the expertise of the Haigis and Kim labs in the parental U01 with the expertise of the Sharpe lab in cancer immunology to identify immune cells that are perturbed with age, and begin to understand how aging impacts cell populations critical to immune surveillance and tumorigenesis in vivo. The proposed studies will create a single-cell atlas of young vs. aged lung at homeostasis and immune cell populations in young vs. aged lung tumors, laying the groundwork for future studies aimed at elucidating mechanisms of diminished anti-tumor control with age.

项目概要本申请是为了响应被确定为 NOT- 的特殊利益通知 (NOSI) 而提交的 CA-23-045。免疫系统可以通过以下方式控制肿瘤生长并塑造肿瘤免疫原性：癌症免疫编辑过程，导致选择能够抵抗的肿瘤细胞变体，避免或抑制抗肿瘤免疫反应并导致临床上明显的肿瘤生长。研究年龄对产生最常见类型的细胞类型的免疫编辑的影响肺癌对于了解肿瘤发生的早期阶段至关重要。主要来源细胞肺腺癌中的肺泡 2 型细胞（AT2 细胞）是远端的祖细胞群肺。在亲本 U01 研究的第一年，我们证明老化的 AT2 细胞在以下方面表现出缺陷：自我更新，表现为培养物中类器官形成减少和修复肺泡的能力受损体内细胞损伤。我们还建立了基因工程小鼠肺模型（GEMM）年轻和老年小鼠的腺癌，并发现免疫细胞比例和细胞因子的改变在老年肿瘤与年轻肿瘤中。在本补充品中，我们试图揭示老年人免疫细胞的变化可能影响 AT2 细胞功能并定义可能有助于免疫细胞改变的环境衰老过程中肿瘤发生增加。我们以两个具体目标来研究这些问题：目标 1：评估肺淋巴细胞和相互作用的肺上皮中与年龄相关的基因调控变化祖先。我们将 1a) 使用多参数流式细胞术来确定与年龄相关的成分肺上皮和免疫细胞的变化以及 1b) 单细胞测序以确定与年龄相关的免疫细胞和肺上皮祖细胞在稳态时相互作用的差异。目标 2：定义肺 GEMM 模型中年轻与老年免疫细胞群的变化腺癌。我们将 1a) 定义 TME 与外周细胞中随年龄变化的免疫细胞群使用流式细胞术和 1b) 剖析肿瘤免疫细胞中的单细胞转录程序年轻小鼠与老年小鼠的比较。该补充材料将汇集 Haigis 和 Kim 实验室的专业知识在亲本 U01 中，利用 Sharpe 实验室在癌症免疫学方面的专业知识来识别免疫细胞随着年龄的增长而受到困扰，并开始了解衰老如何影响对生命至关重要的细胞群体内免疫监视和肿瘤发生。拟议的研究将创建一个单细胞图谱年轻与老年肺的稳态情况以及年轻与老年肺肿瘤中的免疫细胞群，铺设为未来研究奠定基础，旨在阐明抗肿瘤控制减弱的机制年龄。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Age-associated H3K9me2 loss alters the regenerative equilibrium between murine lung alveolar and bronchiolar progenitors.

DOI：
10.1016/j.devcel.2023.10.011
发表时间：
2023-11-01
期刊：
Developmental cell
影响因子：
11.8
作者：
Samuel P. Rowbotham;P. Pessina;Carolina Garcia;Jake Jensen;Yvonne Nguyen;Joon Yoon;Jingyun Li;Irene G. Wong;Caroline G. Fahey;Aaron L. Moye;Joann Chongsaritsinsuk;Roderick Bronson;Shannan J. Ho Sui;Carla F. Kim
通讯作者：
Carla F. Kim