Abstract 3249: Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer

Abstract

Abstract Aberrant myelopoiesis is commonly observed in patients with solid cancers. This results in the production of myeloid-derived suppressive cells (MDSCs) which promote tumor growth and metastasis. However, the molecular mechanisms underlying MDSC development have remained poorly understood. The transcription factor IRF8 is integral for overseeing myelopoietic fate; high IRF8 expression during normal myelopoiesis favors monocytic differentiation and directly inhibits granulocytic differentiation. We recently showed that tumor-derived STAT3/5-activating cytokines downregulate the expression of IRF8 in myeloid cells leading to the accumulation of MDSCs in the periphery, which are primarily granulocytic. However it is unclear if MDSC production is a consequence of IRF8 downregulation in the periphery or upstream in the bone marrow during myelopoiesis. To that end, we utilized a novel mouse model expressing an IRF8-EGFP fusion protein which allowed us to investigate changes in IRF8 expression during both orthotopic and spontaneous mammary tumor growth and progression. Our results showed that: 1) the total granulocyte-monocyte progenitor (GMP) fraction, as with the peripheral MDSC population, was responsive to tumor burden and greatly expanded with increasing tumor size, and 2) IRF8 expression within the total GMPs significantly decreased during tumor growth, reflecting the expansion of a newly defined primarily IRF8lo granulocyte progenitor (GP) population, and 3) tumor-induced GPs were hyper-responsive not only to G-CSF, but also M-CSF to generate a ‘biased’ granulocytic MDSC-like phenotype. Expression of IRF8 in other progenitor populations was not affected, suggesting that IRF8lo GMPs/GPs are a key source of the peripheral MDSC response. Lastly, genetically enforced IRF8 expression in myeloid progenitors of the bone marrow constrained aberrant myelopoiesis during tumor growth, resulting in delayed autochthonous tumor growth and reduced spontaneous lung metastasis. Altogether, these data reinforce the notion that modulation of IRF8 in myeloid progenitors is an early consequence of the neoplastic process and a potential target for therapeutic intervention. NIH R01CA140622 NIH T32CA085183 Citation Format: Colleen S. Netherby, Michelle N. Messmer, Scott I. Abrams. Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3249.