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

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

Epigenetics & Molecular Carcinogenesis

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	109187
Journal	iScience
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.isci.2024.109187
State	Published - Mar 15 2024

Keywords

Cancer
Immunology
Microenvironment

ASJC Scopus subject areas

General

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Tzetzo, S. L., Kramer, E. D., Mohammadpour, H., Kim, M., Rosario, S. R., Yu, H., Dolan, M. R., Oturkar, C. C., Morreale, B. G., Bogner, P. N., Stablewski, A. B., Benavides, F. J., Brackett, C. M., Ebos, J. M. L., Das, G. M., Opyrchal, M., Nemeth, M. J., Evans, S. S., & Abrams, S. I. (2024). Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression. iScience, 27(3), Article 109187. https://doi.org/10.1016/j.isci.2024.109187

Tzetzo, SL, Kramer, ED, Mohammadpour, H, Kim, M, Rosario, SR, Yu, H, Dolan, MR, Oturkar, CC, Morreale, BG, Bogner, PN, Stablewski, AB, Benavides, FJ, Brackett, CM, Ebos, JML, Das, GM, Opyrchal, M, Nemeth, MJ, Evans, SS & Abrams, SI 2024, 'Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression', iScience, vol. 27, no. 3, 109187. https://doi.org/10.1016/j.isci.2024.109187

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title = "Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression",

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 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.",

keywords = "Cancer, Immunology, Microenvironment",

author = "Tzetzo, {Stephanie L.} and Kramer, {Elliot D.} and Hemn Mohammadpour and Minhyung Kim and Rosario, {Spencer R.} and Han Yu and Dolan, {Melissa R.} and Oturkar, {Chetan C.} and Morreale, {Brian G.} and Bogner, {Paul N.} and Stablewski, {Aimee B.} and Benavides, {Fernando J.} and Brackett, {Craig M.} and Ebos, {John M.L.} and Das, {Gokul M.} and Mateusz Opyrchal and Nemeth, {Michael J.} and Evans, {Sharon S.} and Abrams, {Scott I.}",

note = "Publisher Copyright: {\textcopyright} 2024 Roswell Park Comprehensive Cancer Center",

year = "2024",

month = mar,

day = "15",

doi = "10.1016/j.isci.2024.109187",

language = "English (US)",

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T1 - Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression

AU - Tzetzo, Stephanie L.

AU - Kramer, Elliot D.

AU - Mohammadpour, Hemn

AU - Kim, Minhyung

AU - Rosario, Spencer R.

AU - Yu, Han

AU - Dolan, Melissa R.

AU - Oturkar, Chetan C.

AU - Morreale, Brian G.

AU - Bogner, Paul N.

AU - Stablewski, Aimee B.

AU - Benavides, Fernando J.

AU - Brackett, Craig M.

AU - Ebos, John M.L.

AU - Das, Gokul M.

AU - Opyrchal, Mateusz

AU - Nemeth, Michael J.

AU - Evans, Sharon S.

AU - Abrams, Scott I.

PY - 2024/3/15

Y1 - 2024/3/15

N2 - 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.

AB - 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.

KW - Cancer

KW - Immunology

KW - Microenvironment

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

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Keywords

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