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

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

  • Cancer Cell. 2023 May 26;S1535-6108(23)00172-1. doi: 10.1016/j.ccell.2023.05.004.
Scott Haston 1,  Estela Gonzalez-Gualda 2,  Samir Morsli 2,  Jianfeng Ge 2,  Virinder Reen 3,  Alexander Calderwood 4,  Ilias Moutsopoulos 4,  Leonidas Panousopoulos 5,  Polina Deletic 6,  Gabriela Carreno 5,  Romain Guiho 5,  Saba Manshaei 5,  Jose Mario Gonzalez-Meljem 7,  Hui Yuan Lim 5,  Daniel J Simpson 8,  Jodie Birch 3,  Husayn A Pallikonda 3,  Tamir Chandra 8,  David Macias 2,  Gary J Doherty 9,  Doris M Rassl 10,  Robert C Rintoul 11,  Massimo Signore 5,  Irina Mohorianu 4,  Arne N Akbar 6,  Jesús Gil 3,  Daniel Muñoz-Espín 12,  Juan Pedro Martinez-Barbera 13
Affiliations

Affiliations

  • 1 Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: scott.haston.13@ucl.ac.uk.
  • 2 Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
  • 3 MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
  • 4 Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
  • 5 Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK.
  • 6 Division of Medicine, University College London, London, UK.
  • 7 Tecnologico de Monterrey, School of Engineering and Sciences, Mexico City, Mexico.
  • 8 MRC Human Generics Unit, University of Edinburgh, Edinburgh, UK.
  • 9 Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • 10 Royal Papworth Hospital NHS Foundation Trust. Cambridge Biomedical Campus, Cambridge CB2 0AY, UK.
  • 11 Royal Papworth Hospital NHS Foundation Trust. Cambridge Biomedical Campus, Cambridge CB2 0AY, UK; Department of Oncology, University of Cambridge, Cambridge, UK; CRUK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK.
  • 12 Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK; CRUK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK. Electronic address: dm742@cam.ac.uk.
  • 13 Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: j.martinez-barbera@ucl.ac.uk.
PMID: 37267953 DOI: 10.1016/j.ccell.2023.05.004
Abstract

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.

Keywords

ABT-737; NSCLC; aging; cancer; endothelial cells; immunosuppression; macrophages; p16INK4a; senescence; senolytic.

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