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

Affiliations

• Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• INSERM U932, Immunity and Cancer, Institut Curie, Paris-Cité University, Paris, France.
• Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• Brain and Body Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• Oncogene Biology Laboratory, Francis Crick Institute, London, UK.
• Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, London, UK.
• Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
• Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

PMID:  39236155  DOI: 10.1126/science.adn0327

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.

年龄是癌症的重要风险因素，但衰老如何影响肿瘤控制仍不清楚。在这项研究中，我们发现免疫系统的衰老，独立于基质和肿瘤的年龄，会推动肺癌的发展。造血衰老增强了紧急骨髓造血，导致髓系祖细胞在肺肿瘤内局部聚集。这些细胞是IL-1⍺的主要来源，而IL-1⍺又促进了髓系反应的增强。与年龄相关的DNMT3A的下降会加剧IL-1⍺的产生。此外，早期干扰IL-1R1的信号传导可以使骨髓造血恢复正常，并减缓肺、结肠和胰腺肿瘤的生长。在人类肿瘤中，我们观察到IL-1⍺表达的单核细胞来源巨噬细胞的富集与年龄、较差的生存率和复发风险相关。这些发现揭示了衰老如何促进癌症，并为治疗提供了可行的策略。

关键词：衰老, IL-1α, IL-1A, IL1A, 癌症, 肿瘤, IL1A购买, IL1A采购, IL1A抗体, IL1A中和抗体, 中和抗体, 佰乐博, 佰乐博生物