Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression
Stephanie L. Tzetzo,
Elliot D. Kramer,
Hemn Mohammadpour,
Minhyung Kim,
Spencer R. Rosario,
Han Yu,
Melissa R. Dolan,
Chetan C. Oturkar,
Brian G. Morreale,
Paul N. Bogner,
Aimee B. Stablewski,
Fernando J. Benavides,
Craig M. Brackett,
John M.L. Ebos,
Gokul M. Das,
Mateusz Opyrchal,
Michael J. Nemeth,
Sharon S. Evans,
Scott I. Abrams
Affiliations
Stephanie L. Tzetzo
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Elliot D. Kramer
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Hemn Mohammadpour
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Minhyung Kim
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Spencer R. Rosario
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Han Yu
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Melissa R. Dolan
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Chetan C. Oturkar
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Brian G. Morreale
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Paul N. Bogner
Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Aimee B. Stablewski
Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Fernando J. Benavides
Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, Houston, TX 77030, USA
Craig M. Brackett
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
John M.L. Ebos
Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Gokul M. Das
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Mateusz Opyrchal
Department of Medicine, Indiana University, Indianapolis, IN 46202, USA
Michael J. Nemeth
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Sharon S. Evans
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Scott I. Abrams
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Corresponding author
Summary: Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.
