1. Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis.
- Author
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Park MD, Le Berichel J, Hamon P, Wilk CM, Belabed M, Yatim N, Saffon A, Boumelha J, Falcomatà C, Tepper A, Hegde S, Mattiuz R, Soong BY, LaMarche NM, Rentzeperis F, Troncoso L, Halasz L, Hennequin C, Chin T, Chen EP, Reid AM, Su M, Cahn AR, Koekkoek LL, Venturini N, Wood-Isenberg S, D'souza D, Chen R, Dawson T, Nie K, Chen Z, Kim-Schulze S, Casanova-Acebes M, Swirski FK, Downward J, Vabret N, Brown BD, Marron TU, and Merad M
- Subjects
- Animals, Mice, Humans, Macrophages immunology, Macrophages metabolism, Interleukin-1beta metabolism, Mice, Inbred C57BL, Interleukin-1alpha metabolism, Interleukin-1alpha genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, Signal Transduction, Hematopoiesis, Myelopoiesis, Aging, Lung Neoplasms pathology, Lung Neoplasms metabolism, Lung Neoplasms genetics, DNA Methyltransferase 3A
- 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.
- Published
- 2024
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