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

The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis 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 tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.

Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.

Declaration of interests J.G. has acted as a consultant for Unity Biotechnology, Geras Bio, Myricx Pharma, and Merck KGaA. J.G. owns equity in Geras Bio. J.G. is a named inventors in an MRC patent and a named inventor in another Imperial College patents, both related to senolytic therapies (the patents are not related to the work presented here). Unity Biotechnology, Myricx Pharma, and Pfizer have funded research in J.G.’s laboratory (unrelated to the work presented here).