Relevance of Interferon Regulatory Factor-8 Expression in Myeloid–Tumor Interactions

Abstract

Perturbations in myelopoiesis are a common feature in solid tumor biology, reflecting the central premise that cancer is not only a localized affliction but also a systemic disease. Because the myeloid compartment is essential for the induction of adaptive immunity, these alterations in myeloid development contribute to the failure of the host to effectively manage tumor progression. These "dysfunctional" myeloid cells have been coined myeloid-derived suppressor cells (MDSCs). Interestingly, such cells not only arise in neoplasia but also are associated with many other inflammatory or pathologic conditions. MDSCs affect disease outcome through multiple mechanisms, including their ability to mediate generalized or antigen-specific immune suppression. Consequently, MDSCs pose a significant barrier to effective immunotherapy in multiple disease settings. Although much interest has been devoted to unraveling mechanisms by which MDSCs mediate immune suppression, a large gap has remained in our understanding of the mechanisms that drive their development in the first place. Investigations into this question have identified an unrecognized role of interferon regulatory factor-8 (IRF-8), a member of the IRF family of transcription factors, in tumor-induced myeloid dysfunction. Ordinarily, IRF-8 is involved in diverse stages of myelopoiesis, namely differentiation and lineage commitment toward monocytes, dendritic cells, and granulocytes. Several recent studies now support the hypothesis that IRF-8 functions as a "master" negative regulator of MDSC formation in vivo. This review focuses on IRF-8 as a potential target suppressed by tumors to cripple normal myelopoiesis, redirecting myeloid differentiation toward the emergence of MDSCs. Understanding the bases by which neoplasia drives MDSC accumulation has the potential to improve the efficacy of therapies that require a competent myeloid compartment.

The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production

“…Importantly, as in mouse models, MDSC presence in human cancer carries significant prognostic value (8, 11). Intriguingly, PMN-MDSCs predominate in both tumor models and cancer patients (12, 13); yet, the mechanisms behind this bias have remained incompletely understood (12). Thus, despite advances in our understanding of the importance of MDSCs in neoplasia, there is much less known regarding the precise origin of MDSCs, why PMN-MDSCs dominate the response and what transcriptional events govern this decision.…”

“…The production of and subsequent differentiation of GMPs are events regulated by lineage-instructive transcription factors. One such transcription factor, interferon regulatory factor-8 (IRF8), is specifically expressed at this stage in myeloid development and is hypothesized to dictate GMP differentiation into either granulocytes (IRF8 lo ) or monocytes (IRF8 hi ) (13, 16–18). This essential role for IRF8 was revealed using IRF8-deficient (IRF8 −/− ) mice.…”

Antitumor Effects of Epidrug/IFNα Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells

“…Indeed, the ARI-induced DC activated phenotype correlated well with the enhanced capability of these cells to specifically migrate toward ARI-treated colorectal cancer cells. One of the most important factors regulating DCcancer cell interactions is IRF8 (49), which acts through epigenetic regulation (50). We previously reported that IRF8 expression is progressively downmodulated during melanoma growth in mice and in human metastatic melanoma cells with respect to primary tumors.…”

A Call for Epidemiological Research on Myeloid-Derived Suppressor Cells in Ovarian Cancer: A Review of the Existing Immunological Evidence and Suggestions for Moving Forward

“…In an effort to understand MDSC accumulation in cancer, a number of studies have analyzed potential genetic and molecular factors. Several studies have reported interferon regulatory factor-8 (IRF-8), as well as the STAT family of transcription factors (STAT1, STAT3, STAT5, STAT6), as having potential roles in their development (11, 20–24). IRF-8 has been shown to be downregulated, resulting in increased levels of MDSCs (20–24).…”