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

Matthew D Park, Jessica Le Berichel, 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, Laszlo Halasz, Clotilde Hennequin, Theodore Chin, Earnest P Chen, Amanda M Reid, Matthew Su, Ashley Reid Cahn, Laura L Koekkoek, Nicholas Venturini, Shira Wood-Isenberg, Darwin D'souza, Rachel Chen, Travis Dawson, Kai Nie, Zhihong Chen, Seunghee Kim-Schulze, Maria Casanova-Acebes, Filip K Swirski, Julian Downward, Nicolas Vabret, Brian D Brown, Thomas U Marron, Miriam Merad

Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · pubmed

Paper

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.

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Research summary

The paper investigates the mechanisms by which hematopoietic aging contributes to cancer progression, specifically through the lens of emergency myelopoiesis and IL-1⍺ signaling. While it addresses an important aspect of aging and its relationship to cancer, it primarily focuses on the consequences of aging rather than directly targeting the root causes of aging itself. The findings provide solid insights into the aging-cancer connection and suggest potential therapeutic strategies, but they do not fundamentally alter our understanding of aging or lifespan extension. Thus, while relevant, the impact is limited.

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