Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis
Matthew D. Park, Jessica Le Bérichel, Pauline Hamon, C. Matthias Wilk, Meriem Belabed, Nader Yatim, Alexis Saffon, Jesse Boumelha, Chiara Falcomatà, Alexander Tepper, Samarth Hegde, Raphaël Mattiuz, Brian Y. Soong, Nelson M. LaMarche, Frederika Rentzeperis, Leanna Troncoso, László Halász, C. Hennequin, Theodore Chin, Earnest P. Chen, Amanda M. Reid, Matthew Su, Ashley Reid, Laura L. Koekkoek, Nicholas Venturini, Shira Wood-isenberg, Darwin D’souza, Rachel Chen, Travis Dawson, Kai Nie, Zhihong Chen, Seunghee Kim‐Schulze, María Casanova-Acebes, Filip K. Świrski, Julian Downward, Nicolas Vabret, Brian D. Brown, Thomas U. Marron, Miriam Mérad
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.