Lung adenocarcinoma (LUAD) arises from intricate interconnections between transformed cells and a permissive tumour microenvironment. In a previous study (Haston et al., Cancer Cell 2023), we found a population of targetable senescence macrophages playing a key role in lung carcinogenesis and, notably, accumulating in naturally aged lungs in the absence of oncogenic stress. While the incidence of LUAD increases with age, the composition of an aged microenvironment and how it relates to lung cancer initiation and progression remains incompletely understood.

Our work employs three different murine models of lung carcinogenesis, tumour burden analyses (2D/3D micro-CT), bulk and single-cell RNAseq transcriptomics, and multiplexed histopathology analyses.

Here, we investigated how ageing modulates the landscape of senescent cells (SnCs) in normal lungs prior tumour initiation and during cancer development. To address this, we employed distinct cohorts of young (~3-months-old) and aged (~18-months-old) p16-FDR mice. In this model, mCherry and the diphtheria toxin receptor (DTR) are expressed under the control of the Cdkn2a promoter (encoding for p16INK4A) to selectively trace and eliminate SnCs in vivo. By leveraging three mouse models of LUAD based on the p16-FDR allele, including genetically-engineered mice (KrasG12D), orthotopic transplantation of lung cancer KP cells (KrasG12D;Trp53fl/fl) and carcinogen-induced LUAD using N-methyl-N-nitrosourea, we show that the selective ablation of SnCs in aged lungs with pharmacogenetic interventions ameliorates tumorigenesis. Our results highlight the impact of aging on remodelling a microenvironment featured by immune senescent ecosystems, including specific populations of macrophages deriving from circulating monocytes (p16+, L6YC-, MHC-II-), gamma delta T cells (p16+, CD11b+, GdTCR+), and dendritic cells (p16+, CD11b+, CD11c+) that account for the highest proportions of differentially expressed genes in scRNAseq analyses. Interestingly, age-associated senescent populations drive liver metastasis of lung cancer cells that is reduced upon senolytic DT administration.

This study establishes a conceptual framework for elucidating the contribution of age-associated senescent cell ecosystems within the tumour microenvironment to promote lung cancer progression and metastasis, and identifies a potential translational platform through selective targeting of an immunosuppressive, tumour-promoting senescent niche induced by physiological aging.

Munoz-Espin laboratory was supported by a CRUK Program Foundation Award (C62187/A29760), by a CRUK Early Detection OHSU Project Award (C62187/A26989), and a MRC New Investigator Research Grant (NIRG) (MR/R000530/1). D.M-E. was funded by a CRUK Cambridge Major Centre Award and University of Cambridge.