Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies. Isolation of YFP-positive (tumour cells), mCherry-positive (p16INK4a-expressing cells) and YFP/mCherry-negative (remainder of the lung) cells from KrasG12D/+; p16FDR/+; Rosa26loxP-STOP-loxP-YFP mice induced to form lung tumours by intranasal AdCre administration. Cells isolated and subjected to bulk RNA-sequencing 8 weeks post tumour initiation.