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

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 3

Reduced IRF8 expression in macrophages leads to increased spontaneous lung metastasis after surgical resection of the primary tumor.

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Reduced IRF8 expression in macrophages leads to increased spontaneous lu...
As in Figure 2, recipient mice were implanted with 4T1 tumor cells and, when the primary tumor volume reached ~100 mm3, it was removed. (A) Mean primary tumor volumes on the day of surgery. (B) Thirty-one to 36 days after surgery, lungs were collected and weighed. (C) Representative photomicrographs of H&E-stained whole lung tissue (left), with a corresponding gray scale image with lung metastases shaded in brown (right). Scale bar: 6 mm. (D–F) Lung metastatic burden in WT vs. IRF8-cKO mice was quantified and reported as percent tumor burden in the lungs (D); quantification of discrete foci (E), similar to Figure 2; and average size of lung lesions (F). H&E-stained slides were analyzed in a blinded-manner for data in D–F. n = 10–11/group in panels A, B, and D–F, and statistical significance was determined by a 2-tailed Mann-Whitney U test. *P < 0.05.