Senescent alveolar macrophages promote early-stage lung tumorigenesis

Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cx...

Full description

Saved in:
Bibliographic Details
Published inCancer cell Vol. 41; no. 7; pp. 1261 - 1275.e6
Main Authors Prieto, Luis I., Sturmlechner, Ines, Graves, Sara I., Zhang, Cheng, Goplen, Nick P., Yi, Eunhee S., Sun, Jie, Li, Hu, Baker, Darren J.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 10.07.2023
Subjects
aging
alveolar macrophages
Animals
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
cytotoxic T cells
Humans
Lung - metabolism
Lung Neoplasms - genetics
Macrophages, Alveolar - metabolism
Mice
senolytic
Tumor Microenvironment
senolytic
cellular senescence
aging
alveolar macrophages
cytotoxic T cells
Online AccessGet full text

Cover

More Information
Summary:Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease. [Display omitted] •Senescent cells accelerate spontaneous KrasLA1-driven lung tumorigenesis•Senescent alveolar macrophages accumulate in aged and tumorous tissue•Surprisingly, knocking out p16INK4a or p21Cip1 delays neoplasia in KrasLA1 mice•Senescent alveolar macrophages counteract cytotoxic T cell accumulation Prieto et al. causally implicate the cellular senescence program in the innate component of the immune system. Senescent alveolar macrophages with tumor-promoting qualities accumulate early in Kras-driven neoplasia, promoting tumorigenesis by adjusting the antitumor T cell response. These senescent macrophages also accumulate with natural age and occur in human NSCLC.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
L.I.P. and D.J.B designed experiments and wrote the manuscript. L.I.P performed most of the experiments. I.S. assisted and performed flow cytometry and in vitro experiments. L.I.P., I.S., C.Z., N.P.G., J.S., and H.L. performed single cell RNA-seq bioinformatics data processing. S.G. helped with assessments in immunofluorescence experiments. E.Y. performed histopathology assessments on all tumor lesions and acquired human NSCLC sample. All authors discussed results and edited the manuscript writing and figures. D.J.B. conceived, directed, and supervised all aspects of the study.
Author contributions
ISSN:1535-6108
1878-3686
1878-3686
DOI:10.1016/j.ccell.2023.05.006