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 2

Reduced IRF8 expression in macrophages leads to increased 4T1 spontaneous lung metastasis.

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Reduced IRF8 expression in macrophages leads to increased 4T1 spontaneou...
(A) Experimental design for the BM chimera tumor model. CB6F1 mice (H-2b/d) were lethally irradiated and then transplanted with WT, IRF8-cKO (Lyz2-CreIRF8fl/fl), or F1 T cell–depleted BM cells. Eight weeks after transplant, reconstitution was determined, followed by tumor implantation. (B) Flow cytometry plots of the reconstituted WT, IRF8-cKO, and F1 genotypes, as determined by peripheral blood analysis 8 weeks after transplant. (C) The chimeric recipients were then implanted with 4T1 cells (5 × 104) in the fourth mammary gland, and tumor growth was measured. (D) End-point tumor volumes for WT or IRF8-cKO hosts, which were not significant. (E) Lungs were collected ~30 days after tumor implantation for histopathologic analyses. Whole lung sections were H&E stained and analyzed in a blinded manner for the number of metastatic foci. Metastatic counts beyond 50 were considered too numerous to count accurately and, thus, are recorded as >50. Metastasis in the IRF8-cKO recipients, compared with the WT controls, was statistically significant by a 2-tailed Mann-Whitney U test (mean ± SEM of 21–23 mice per group, *P < 0.05). Data in C–E were compiled from 4 separate experiments.