Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis
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.
Authors
- Kai Nie (ORCID: https://orcid.org/0000-0002-8253-9688)
- Raphaël Mattiuz (ORCID: https://orcid.org/0000-0002-3292-1635)
- Rachel Chen (ORCID: https://orcid.org/0009-0004-0021-2561)
- Pauline Hamon (ORCID: https://orcid.org/0000-0002-6776-1635)
- Julian Downward (ORCID: https://orcid.org/0000-0002-2331-4729)
- Earnest P. Chen (ORCID: https://orcid.org/0000-0002-1626-5551)
- C. Matthias Wilk (ORCID: https://orcid.org/0000-0001-5429-7143)
- Leanna Troncoso (ORCID: https://orcid.org/0000-0003-2529-9267)
- María Casanova-Acebes (ORCID: https://orcid.org/0000-0002-5790-1163)
- Amanda M. Reid
- Nicholas Venturini (ORCID: https://orcid.org/0000-0002-3769-5956)
- Theodore Chin (ORCID: https://orcid.org/0000-0003-1720-4117)
- Filip K. Świrski (ORCID: https://orcid.org/0000-0002-3163-9152)
- Matthew D. Park (ORCID: https://orcid.org/0000-0003-3488-3262)
- Samarth Hegde (ORCID: https://orcid.org/0000-0001-6319-0372)
- Darwin D’souza (ORCID: https://orcid.org/0000-0002-1943-5173)
- Alexander Tepper (ORCID: https://orcid.org/0000-0003-1384-9241)
- László Halász (ORCID: https://orcid.org/0000-0003-4726-7012)
- Ashley Reid (ORCID: https://orcid.org/0000-0002-7741-6958)
- Brian Y. Soong (ORCID: https://orcid.org/0000-0003-4647-7704)
- Jessica Le Bérichel (ORCID: https://orcid.org/0000-0003-0846-3280)
- Seunghee Kim‐Schulze (ORCID: https://orcid.org/0000-0003-0192-4400)
- Thomas U. Marron (ORCID: https://orcid.org/0000-0001-5903-8191)
- Nader Yatim (ORCID: https://orcid.org/0000-0001-5326-1624)
- Nicolas Vabret (ORCID: https://orcid.org/0000-0002-0846-1819)
- Nelson M. LaMarche
- Brian D. Brown (ORCID: https://orcid.org/0000-0002-3670-8778)
- Miriam Mérad (ORCID: https://orcid.org/0000-0002-4481-7827)
- Chiara Falcomatà (ORCID: https://orcid.org/0000-0001-9269-2582)
- Frederika Rentzeperis (ORCID: https://orcid.org/0000-0001-9797-1134)
- C. Hennequin (ORCID: https://orcid.org/0000-0001-9874-2704)
- Meriem Belabed (ORCID: https://orcid.org/0000-0002-3210-1581)
- Laura L. Koekkoek
- Travis Dawson (ORCID: https://orcid.org/0000-0002-9609-793X)
- Jesse Boumelha (ORCID: https://orcid.org/0000-0001-7635-2537)
- Alexis Saffon (ORCID: https://orcid.org/0000-0001-7771-4229)
- Zhihong Chen (ORCID: https://orcid.org/0000-0001-7403-7015)
- Shira Wood-isenberg
- Matthew Su
Institutions
- Allen Institute for Brain Science (US)
- Institute of Cancer Research (GB)
- Inserm (FR)
- Université Paris Cité (FR)
- The Francis Crick Institute (GB)
- Immunité et Cancer (FR)
- Tisch Hospital (US)
- CRUK Lung Cancer Centre of Excellence (GB)
- Institut Curie (FR)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1126/science.adn0327
- Citations
- 102
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 24.53
Funders
- National Science Foundation
- Cancer Research Institute
- Bristol-Myers Squibb
- AstraZeneca
- Icahn School of Medicine at Mount Sinai
- Deutsches Krebsforschungszentrum
- Regeneron Pharmaceuticals
- Celldex Therapeutics
- Atara Biotherapeutics
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- G1 Therapeutics
- Glenmark Pharmaceuticals
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Astellas Pharma
- Technische Universität München
- Swiss Cancer Research Foundation
- Genentech
- National Cancer Institute