| Summary: | Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of <i>Irf8</i> leads to massive accumulation of CD11b<sup>+</sup>Gr1<sup>+</sup> immature myeloid cells (IMCs), particularly the CD11b<sup>+</sup>Ly6C<sup>hi/+</sup>Ly6G<sup>−</sup> polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, <i>Irf8</i> is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b<sup>+</sup> Ly6G<sup>+</sup>Ly6C<sup>lo</sup> monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases.
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