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

• 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
• 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

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.

项目摘要 本申请是为了回应特别利益通知（NOSI）而提交的，该通知被确定为不- CA-23-045免疫系统可以通过免疫原性来控制肿瘤生长并形成肿瘤免疫原性。 癌症免疫编辑过程，导致选择可以抵抗的肿瘤细胞变体， 避免或抑制抗肿瘤免疫应答，并导致临床上明显的肿瘤生长。 研究年龄对细胞类型中免疫编辑的影响，这种细胞类型会引起最常见的免疫缺陷。 肺癌对于了解肿瘤发生的早期阶段至关重要。主要的起源细胞 在肺腺癌中，肺泡2型细胞（AT 2细胞）是肺腺癌远端的祖细胞群， 肺。在亲本U 01研究的第一年，我们证明了老化的AT 2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。我们还建立了一个基因工程小鼠模型（GEMM）， 腺癌的年轻和老年小鼠，并确定了改变免疫细胞比例和细胞因子 与年轻肿瘤相比。在这篇补充文章中，我们试图揭示老年人免疫细胞的变化。 可能影响AT 2细胞功能并定义免疫细胞中可能有助于 在衰老过程中增加肿瘤发生。我们在两个具体目标中研究这些问题：目标1： 评估肺淋巴细胞和相互作用的肺上皮细胞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）单细胞测序以鉴定年龄相关的 免疫细胞和肺上皮祖细胞在稳态时相互作用的差异。目标二： 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与外周中随年龄变化的免疫细胞群 使用流式细胞术和1b）剖析来自肿瘤的免疫细胞中的单细胞转录程序 年轻和年老的老鼠。这一补充将汇集海吉斯和金实验室的专业知识 在父母U 01与夏普实验室在癌症免疫学的专业知识，以确定免疫细胞 随着年龄的增长而受到干扰，并开始了解衰老如何影响细胞群， 免疫监视和体内肿瘤发生。拟议的研究将创建一个单细胞图谱， 处于稳态的年轻与老年肺以及年轻与老年肺肿瘤中的免疫细胞群，产蛋 为未来的研究奠定基础，旨在阐明降低抗肿瘤控制的机制， 年龄