Profiling immune cells in aged lung tumor initiation

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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.