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  3. In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma

In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma

  • Nat Commun. 2023 Jan 17;14(1):143. doi: 10.1038/s41467-022-35701-8.
Seiji Taniguchi 1 2 3,  Takahiro Matsui 4 5,  Kenji Kimura 3,  Soichiro Funaki 3,  Yu Miyamoto 1 2,  Yutaka Uchida 1 2,  Takao Sudo 1 2,  Junichi Kikuta 1 2 6,  Tetsuya Hara 7,  Daisuke Motooka 8 9,  Yu-Chen Liu 9,  Daisuke Okuzaki 8 9,  Eiichi Morii 10,  Noriaki Emoto 7,  Yasushi Shintani 3,  Masaru Ishii 11 12 13
Affiliations

Affiliations

  • 1 Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
  • 2 Laboratory of Immunology and Cell Biology, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
  • 3 Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
  • 4 Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. matsuit@molpath.med.osaka-u.ac.jp.
  • 5 Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. matsuit@molpath.med.osaka-u.ac.jp.
  • 6 Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan.
  • 7 Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Higashinada, Kobe, 658-8558, Japan.
  • 8 Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
  • 9 Laboratory of Human Immunology (Single Cell Genomics), WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
  • 10 Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
  • 11 Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. mishii@icb.med.osaka-u.ac.jp.
  • 12 Laboratory of Immunology and Cell Biology, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan. mishii@icb.med.osaka-u.ac.jp.
  • 13 Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan. mishii@icb.med.osaka-u.ac.jp.
PMID: 36650150 DOI: 10.1038/s41467-022-35701-8
Abstract

Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung Cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung Cancer model and human carcinoma samples, that AMs support Cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of Activin A, a homodimer of INHBA. Accordingly, Follistatin, an antagonist of Activin A is able to inhibit lung Cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/Activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.

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