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IFN regulatory factor–8 expression in macrophages governs an antimetastatic program
Danielle Y.F. Twum, … , Michael J. Nemeth, Scott I. Abrams
Danielle Y.F. Twum, … , Michael J. Nemeth, Scott I. Abrams
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e124267. https://doi.org/10.1172/jci.insight.124267.
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Research Article Immunology Oncology

IFN regulatory factor–8 expression in macrophages governs an antimetastatic program

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Abstract

High macrophage infiltration in cancer is associated with reduced survival in animal models and in patients. This reflects a shift in the macrophage response from a tumor-suppressive to tumor-supportive program governed by transcriptional events regulated by the inflammatory milieu. Although several transcription factors are known to drive a prometastatic program, those that govern an antimetastatic program are less understood. IFN regulatory factor-8 (IRF8) is integral for macrophage responses against infections. Using a genetic loss-of-function approach, we tested the hypothesis that IRF8 expression in macrophages governs their capacity to inhibit metastasis. We found that: (a) metastasis was significantly increased in mice with IRF8-deficient macrophages; (b) IRF8-deficient macrophages displayed a program enriched for genes associated with metastasis; and (c) lower IRF8 expression correlated with reduced survival in human breast and lung cancer, as well as melanoma, with high or low macrophage infiltration. Thus, a macrophagehiIRF8hi signature was more favorable than a macrophagehiIRF8lo signature. The same held true for a macrophageloIRF8hi vs. a macrophageloIRF8lo signature. These data suggest that incorporating IRF8 expression levels within a broader macrophage signature or profile strengthens prognostic merit. Overall, to our knowledge, our findings reveal a previously unrecognized role for IRF8 in macrophage biology to control metastasis or predict outcome.

Authors

Danielle Y.F. Twum, Sean H. Colligan, Nicholas C. Hoffend, Eriko Katsuta, Eduardo Cortes Gomez, Mary Lynn Hensen, Mukund Seshadri, Michael J. Nemeth, Scott I. Abrams

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Figure 5

Reduced IRF8 expression in macrophages associates with an enrichment of metastasis-associated genes.

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Reduced IRF8 expression in macrophages associates with an enrichment of ...
Transcriptome analysis of BMDMs from WT (n = 2 biologic replicates) or IRF8-cKO (n = 2 biologic replicates) mice after treatment with IFN-γ (100 U/ml for 24 hours) to maximize IRF8 induction. (A) GSEA for positively enriched genes in BMDMs from the IRF8-cKO model. NES, normalized enrichment score. (B) Overrepresented biologic processes showing genes upregulated in BMDMs from IFN-γ–treated IRF8-cKO mice compared with the IFN-γ–treated WT controls, as determined by gene ontology (GO) analysis. (C) Heatmaps depicting a subset of upregulated genes involved in immune response, cell migration, and chemotaxis (as boxed in B) of BMDMs from the same groups in A and B. Full heatmaps can be found in Supplemental Figure 9. (D) Validation of the indicated genes by qPCR analyses (mean ± SEM of 6 replicates pooled from 2 biologic or independent experiments). Statistical analysis was determined by a 2-tailed Mann-Whitney U test. *P < 0.05.
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