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

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Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis
Science ( IF 44.7 ) Pub Date : 2024-09-05 , DOI: 10.1126/science.adn0327
Matthew D Park _{1,

2,

3} , Jessica Le Berichel _{1,

2,

3} , Pauline Hamon _{1,

2,

3} , C Matthias Wilk _{1,

2,

3} , Meriem Belabed _{1,

2,

3} , Nader Yatim _{1,

2,

3} , Alexis Saffon _{1,

2,

3,

4} , Jesse Boumelha _{1,

2,

3} , Chiara Falcomatà _{1,

2,

3,

5} , Alexander Tepper _{1,

2,

3,

5} , Samarth Hegde _{1,

2,

3} , Raphaël Mattiuz _{1,

2,

3} , Brian Y Soong _{1,

2,

3} , Nelson M LaMarche _{1,

2,

3} , Frederika Rentzeperis _{1,

2,

3} , Leanna Troncoso _{1,

2,

3} , Laszlo Halasz _{1,

2,

3} , Clotilde Hennequin _{1,

2,

3} , Theodore Chin _{1,

2,

3} , Earnest P Chen _{1,

2,

3} , Amanda M Reid _{1,

2,

3} , Matthew Su _{1,

2,

3} , Ashley Reid Cahn _{1,

2,

3} , Laura L Koekkoek _{1,

2,

6} , Nicholas Venturini _{1,

2,

3} , Shira Wood-Isenberg _{1,

2,

3} , Darwin D'souza _{1,

2,

7} , Rachel Chen _{1,

2,

7} , Travis Dawson _{1,

2,

7} , Kai Nie _{1,

2,

7} , Zhihong Chen _{1,

2,

7} , Seunghee Kim-Schulze _{1,

2,

7} , Maria Casanova-Acebes _{1,

2,

3} , Filip K Swirski _{1,

2,

6,

8} , Julian Downward _{9,

10} , Nicolas Vabret _{1,

2,

3} , Brian D Brown _{1,

2,

3,

5} , Thomas U Marron _{1,

2,

3,

11,

12} , Miriam Merad _{1,

2,

3,

7}

Affiliation

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.

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. Here, 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 IL-1⍺ that drives the enhanced myeloid response. The age-associated decline of DNMT3A enhances IL-1⍺ production, and disrupting IL-1R1 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.

中文翻译：

造血衰老通过助长 IL-1 驱动的紧急骨髓生成来促进癌症

年龄是癌症的主要危险因素，但衰老如何影响肿瘤控制仍不清楚。在这里，我们确定免疫系统的衰老，无论基质和肿瘤的年龄如何，都会推动肺癌的进展。造血衰老增强紧急骨髓生成，导致肺肿瘤中髓系祖细胞样细胞的局部积累。这些细胞是 IL-1⍺ 的主要来源，可驱动增强的髓系反应。DNMT3A 与年龄相关的下降增强了 IL-1⍺ 的产生，并在肿瘤发展的早期破坏了 IL-1R1 信号传导，使骨髓生成正常化并减缓了肺、结肠和胰腺肿瘤的生长。在人类肿瘤中，我们确定了表达 IL-1 的单核细胞衍生巨噬细胞的富集，这些巨噬细胞与年龄、较差的生存率和复发有关，揭示了衰老如何促进癌症并提供可行的治疗策略。

更新日期：2024-09-05

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