Tumor-derived factors downregulate IRF8 in myeloid progenitors to induce MDSC accumulation.
Major finding: Tumor-derived factors downregulate IRF8 in myeloid progenitors to induce MDSC accumulation.
Clinical relevance: IRF8 levels in MDSCs of breast cancer patients are inversely correlated with MDSC frequency.
Impact: Enhancement of IRF8 expression may reduce MDSC accumulation and potentiate the effects of immunotherapy.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cell populations that inhibit immune responses and facilitate tumor immune evasion. Given that MDSCs are a product of impaired myeloid cell maturation, a process which is normally regulated by interferon regulatory factor 8 (IRF8), Waight and colleagues hypothesized that tumor-mediated downregulation of IRF8 in myeloid cells promotes the development of MDSCs. Indeed, in mammary tumor models, Irf8 expression was specifically reduced in MDSC subsets of tumor-bearing mice, indicating that tumors can promote IRF8 downregulation. A causal relationship between IRF8 loss and MDSC expansion was further suggested by the observations of abnormal expansion of a CD11b+Gr-1+ myeloid cell population capable of strongly suppressing T cell proliferation and increasing tumor growth in Irf8-null mice, and a marked reduction in CD11b+Gr-1+ cell accumulation, tumor growth, and metastasis in Irf8-overexpressing transgenic mice. Tumor-secreted cytokines known to promote MDSC accumulation, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, were found to significantly and rapidly downregulate Irf8 expression in a STAT3- or STAT5-dependent manner, which could be rescued by pharmacologic inhibition of JAK2/STAT3 or STAT5. The potential clinical impact of tumor-mediated IRF8 downregulation was shown by the observation that intracellular IRF8 levels in MDSCs of patients with late-stage breast cancer were inversely correlated with MDSC population size, which in turn was inversely correlated with progression-free and overall survival. In addition to providing mechanistic insight into how tumor-derived factors initiate MDSC development, these findings suggest that preventing STAT-mediated IRF8 downregulation may block MDSC accumulation, boost antitumor immunity, and improve clinical outcomes.