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

Cancer Cell, Volume 41, Issue 7, 10 July 2023, Pages 1242-1260.e6

Scott Haston, Estela Gonzalez-Gualda, Samir Morsli, Jianfeng Ge, Virinder Reen, Alexander Calderwood, Ilias Moutsopoulos, Leonidas Panousopoulos, Polina Deletic, Gabriela Carreno, Romain Guiho, Saba Manshaei, Jose Mario Gonzalez-Meljem, Hui Yuan Lim, Daniel J. Simpson, Jodie Birch, Husayn A. Pallikonda, Tamir Chandra, David Macias, Gary J. Doherty, Doris M. Rassl, Robert C. Rintoul, Massimo Signore, Irina Mohorianu, Arne N. Akbar, Jesús Gil, Daniel Muñoz-Espín, Juan Pedro Martinez-Barbera
senescence, p16INK4a, cancer, NSCLC, senolytic, ABT-737, macrophages, endothelial cells, aging, immunosuppression

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.

17 Jan 2020