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Science, Oct 25 2024, 386 (6720) | https://doi.org/10.1126/science.adn0327
Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis
Matthew D Park 1 2 3, Jessica Le Berichel 1 2 3 #, Pauline Hamon 1 2 3 #, C Matthias Wilk 1 2 3 # , Meriem Belabed 1 2 3 #, Nader Yatim 1 2 3, Alexis Saffon 1 2 3 4, Jesse Boumelha 1 2 3, Chiara Falcomatà 1 2 3 5, Alexander Tepper 1 2 3 5, Samarth Hegde 1 2 3, Raphaël Mattiuz 1 2 3, Brian Y Soong 1 2 3, Nelson M LaMarche 1 2 3, Frederika Rentzeperis 1 3, Leanna Troncoso 1 2 3, Laszlo Halasz 1 2 3, Clotilde Hennequin 1 2 3, Theodore Chin 1 2 3, Earnest P Chen 1 2 3, Amanda M Reid 1 2 3, Matthew Su 1 2 3, Ashley Reid Cahn 1 2 3, Laura L Koekkoek 1 2 6, Nicholas Venturini 1 2 3, Shira Wood-Isenberg 1 2 3, Darwin D'souza 1 2 7, Rachel Chen 1 2 7, Travis Dawson 1 2 7, Kai Nie 1 2 7, Zhihong Chen 1 2 7, Seunghee Kim-Schulze 1 2 7, Maria Casanova-Acebes 1 2 3, Filip K Swirski 1 2 6 8, Julian Downward 9 10, Nicolas Vabret 1 2 3, Brian D Brown 1 2 3 5, Thomas U Marron 1 2 3 11 12, Miriam Merad 1 2 3 7 *
1Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4INSERM U932, Immunity and Cancer, Institut Curie, Paris-Cité University, Paris, France.
5Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6Brain and Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9Oncogene Biology Laboratory, Francis Crick Institute, London, UK.
10Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, London, UK.
11Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4INSERM U932, Immunity and Cancer, Institut Curie, Paris-Cité University, Paris, France.
5Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6Brain and Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9Oncogene Biology Laboratory, Francis Crick Institute, London, UK.
10Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, London, UK.
11Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
#These authors contributed equally
*Corresponding author: correspondence to Miriam Merad
*Corresponding author: correspondence to Miriam Merad
Abstract
Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.
논문정보
- Research article
- 2024년 10월 (BRIC 등록일 2025-01-28)
- 국외 연구진
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