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

Science. 2024 Oct 25;386(6720):eadn0327. doi: 10.1126/science.adn0327. Epub 2024 Oct 25.

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.

MeSH terms

  • Aging* / immunology
  • Animals
  • DNA Methyltransferase 3A* / deficiency
  • Hematopoiesis
  • Humans
  • Interleukin-1alpha* / genetics
  • Interleukin-1alpha* / metabolism
  • Interleukin-1beta / metabolism
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myelopoiesis* / immunology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Signal Transduction

Substances

  • DNA Methyltransferase 3A
  • Interleukin-1alpha
  • Interleukin-1beta