Profiling immune cells in aged lung tumor initiation

项目摘要 本申请是为回应特别利益通知(NOSI)而提出的，该通知被确认为非- CA-23-045。免疫系统可通过以下途径控制肿瘤生长和形成肿瘤免疫原性 癌症免疫编辑过程，其结果是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。 研究年龄对免疫编辑的影响，细胞类型导致最常见的类型 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 肺腺癌是肺泡2型细胞(AT2细胞)，它是位于肺腺癌远端的前体细胞群。 阿龙。在亲代U01研究的第一年，我们证明了老化的AT2细胞在 自我更新，表现为培养中有机物质的形成减少和肺泡修复能力受损 活体细胞损伤。我们还建立了肺的基因工程小鼠模型(GEMM)。 幼年和老年小鼠的腺癌及其免疫细胞比例和细胞因子的改变 在老年人和年轻人的肿瘤中。在这份补充资料中，我们试图揭示老年人免疫细胞的变化 可能影响AT2细胞功能并定义免疫细胞变化的环境可能有助于 在衰老过程中增加肿瘤的发生。我们调查这些问题有两个具体目标：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1)使用多参数流式细胞术来确定与年龄相关的成分 肺上皮细胞和免疫细胞的变化及1b)单细胞测序鉴定年龄相关性 免疫细胞和肺上皮祖细胞在动态平衡时相互作用的差异。目标2： 探讨肺GEMM模型中青年与老年免疫细胞群的变化 腺癌。我们将1)定义TME与外周组织中随年龄变化的免疫细胞群 用流式细胞术和1b)解剖肿瘤免疫细胞中的单细胞转录程序 来自幼鼠和老龄鼠。本增刊将汇集海吉斯实验室和金氏实验室的专业知识。 在亲代U01中与夏普癌症免疫学实验室的专业知识鉴定免疫细胞 他们对年龄感到不安，并开始了解衰老是如何影响对 免疫监测与体内肿瘤发生。拟议的研究将创建一份单细胞图谱 年轻与老年肺的动态平衡和免疫细胞群在年轻与老年肺癌产卵中的比较 为未来旨在阐明抗肿瘤控制减弱的机制的研究奠定了基础 年龄。

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.