Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis

• 成果类型: Article
• 署名作者: Park, Matthew D.; Le Berichel, Jessica; Hamon, Pauline; Wilk, C. Matthias; Belabed, Meriem; Yatim, Nader; Saffon, Alexis; Boumelha, Jesse; Falcomata, Chiara; Tepper, Alexander; Hegde, Samarth; Mattiuz, Raphael; Soong, Brian Y.; Lamarche, Nelson M.; Rentzeperis, Frederika; Troncoso, Leanna; Halasz, Laszlo; Hennequin, Clotilde; Chin, Theodore; Chen, Earnest P.; Reid, Amanda M.; Su, Matthew; Cahn, Ashley Reid; Koekkoek, Laura L.; Venturini, Nicholas; Wood-isenberg, Shira; D'souza, Darwin; Chen, Rachel; Dawson, Travis; Nie, Kai; Chen, Zhihong; Kim-Schulze, Seunghee; Casanova-Acebes, Maria; Swirski, Filip K.; Downward, Julian; Vabret, Nicolas; Brown, Brian D.; Marron, Thomas U.; Merad, Miriam
• 署名单位: Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Universite Paris Cite; Universite PSL; UNICANCER; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Francis Crick Institute; University of London; University College London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Yale University; Yale University; Centro Nacional de Investigaciones Oncologicas (CNIO)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11402
• DOI: 10.1126/science.adn0327
• 发表日期: 2024-10-25
• 关键词: clonal hematopoiesis; stem-cells; alveolar macrophages; myeloid differentiation; viral mimicry; lung; drives; senescence; mutations; melanoma

摘要

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 alpha, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1 alpha 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 alpha-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.