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Abstract A big challenge in oncology is tumor heterogeneity, as the same type of tumor can manifest differently across patients. Our current cancer therapies focus on targeting malignant cells without considering how the tumor microenvironment influence tumorigenesis or changes in response to treatment. Therefore, identifying effective therapies that restrict tumor growth and progression while restoring optimal tissue and organ function is imperative. Here, we propose a potential strategy to delay the frequency of lung tumorigenesis and reduce progression by selectively targeting tumor-promoting senescent cells that arise with advancing age, prolonging antitumor immunity. Using lung tumor-prone mice, we found that senescent cells, specifically senescent alveolar macrophages, accumulate early in hyperplastic lesions. Mechanistically, these macrophages upregulate the cell cycle regulator p16Ink4a; express the cell surface protein CXCR1; they are distinct from other established subsets; are sensitive to senolytic interventions; have a tumor-promoting secretome, including SPP1; and express immunosuppressive factors that modulate the antitumor immune response. Selective clearance of senescent macrophages attenuates adenoma development, indicating they, at least in part, promote tumorigenesis. Importantly, we observed alveolar macrophages with these properties accumulating in treatment-naive human early-stage lung adenocarcinoma in situ, indicating that the cellular senescence program in macrophages is a conserved etiology. We also found that senescent alveolar macrophages accumulate in otherwise naturally aged normal mouse lungs and their persistence correlates with increased inflammation. Collectively, our findings suggest that targeting senescent macrophages may constitute a potential therapeutic intervention to postpone or attenuate lung cancer during the early stages of the disease. Citation Format: Luis I. Prieto. Senescent macrophages drive tumorigenesis by limiting antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2972.
Luis I. Prieto (Fri,) studied this question.