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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...
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Published in: | Cancer cell 2023-07, Vol.41 (7), p.1261-1275.e6 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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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.
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•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. |
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ISSN: | 1535-6108 1878-3686 1878-3686 |
DOI: | 10.1016/j.ccell.2023.05.006 |