Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis

Affiliations

• Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
• Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK
• Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
• Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain
• Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

PMID:  39378878  DOI: 10.1016/j.cell.2024.09.016

Abstract

Breast disseminated cancer cells (DCCs) can remain dormant in the lungs for extended periods, but the mechanisms limiting their expansion are not well understood. Research indicates that tissue-resident alveolar macrophages suppress breast cancer metastasis in lung alveoli by inducing dormancy. Through ligand-receptor mapping and intravital imaging, it was found that alveolar macrophages express transforming growth factor (TGF)-b2. This expression, along with persistent macrophage-cancer cell interactions via the TGF-bRIII receptor, maintains cancer cells in a dormant state. Depleting alveolar macrophages or losing the TGF-b2 receptor in cancer cells triggers metastatic awakening. Aggressive breast cancer cells are either suppressed by alveolar macrophages or evade this suppression by avoiding interaction and downregulating the TGF-b2 receptor. Restoring TGF-bRIII in aggressive cells reinstates TGFb2-mediated macrophage growth suppression. Thus, alveolar macrophages act as a metastasis immune barrier, and downregulation of TGF-b2 signaling allows cancer cells to overcome macrophage-mediated growth suppression.

乳腺转移癌细胞（DCCs）可以在肺部长时间保持休眠状态，但限制其扩散的机制尚不明确。研究表明，组织驻留的肺泡巨噬细胞通过诱导休眠来抑制乳腺癌在肺泡中的转移。通过配体-受体映射和体内成像发现，肺泡巨噬细胞表达TGF-β2。这种表达以及巨噬细胞与癌细胞之间通过TGF-βRIII受体的持续相互作用，维持了癌细胞的休眠状态。如果去除肺泡巨噬细胞或癌细胞失去TGF-β2受体，就会触发转移性觉醒。侵袭性乳腺癌细胞要么被肺泡巨噬细胞抑制，要么通过避免相互作用和下调TGF-β2受体来逃避这种抑制。恢复侵袭性细胞中的TGF-βRIII可以重新建立TGF-β2介导的巨噬细胞生长抑制。因此，肺泡巨噬细胞充当了转移的免疫屏障，而TGF-β2信号通路的下调使癌细胞能够克服巨噬细胞介导的生长抑制。