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

doi:10.1016/j.isci.2024.109187

Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression

iScience. 2024 Feb 10;27(3):109187. doi: 10.1016/j.isci.2024.109187. eCollection 2024 Mar 15.

Authors

Stephanie L Tzetzo¹, Elliot D Kramer¹, Hemn Mohammadpour², Minhyung Kim³, Spencer R Rosario⁴, Han Yu⁴, Melissa R Dolan⁵, Chetan C Oturkar⁵, Brian G Morreale¹, Paul N Bogner⁶, Aimee B Stablewski⁷, Fernando J Benavides⁸, Craig M Brackett², John M L Ebos^{9

10}, Gokul M Das⁵, Mateusz Opyrchal¹¹, Michael J Nemeth¹, Sharon S Evans¹, Scott I Abrams¹

Affiliations

¹ Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
² Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
³ Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁴ Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁵ Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁶ Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁷ Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁸ Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
¹⁰ Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
¹¹ Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.

Abstract

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 CD68^hiIRF8^loG-CSF^hi 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.

Keywords: Cancer; Immunology; Microenvironment.