Alterations in myelopoiesis are a well-recognized manifestation of tumor progression across different cancer
types, including breast cancer. This is due in part to the chronic inflammatory state associated with the disease
process. A major outcome of this altered myeloid response is the production of myeloid-derived suppressor
cells (MDSCs). MDSCs consist of immature myeloid populations, reflecting cells of monocytic and granulocytic
origin, that are highly immune suppressive and thus act as roadblocks to the efficacy of diverse therapies, and
immunotherapy in particular. Thus, efforts to understand how MDSCs develop or function are instrumental for
the discovery of new strategies that block their role as negative regulators of anti-tumor immunity. While much
is known about how MDSCs execute their functions, much less is known about how they develop or acquire
such suppressive behavior. To that end, previous work in our laboratory has identified an important role for the
myeloid-dependent transcription factor, interferon regulatory factor-8 (IRF8) as a negative regulator of MDSC
production. Through the secretion of tumor-derived myelopoietic growth factors, we showed that tumors inhibit
IRF8 expression in bone marrow progenitors, leading to the generation of MDSCs. A causal role for IRF8 was
demonstrated through in vivo proof-of-concept IRF8 genetic loss- or gain-of-function studies. Moreover, the
overexpression of IRF8 in the myeloid system through such gain-of-function approaches reduced MDSC
numbers and boosted the efficacy of immune checkpoint inhibitor (ICI)-based therapy. These data suggest that
the IRF8 pathway may serve as a druggable target and strategies designed to sustain myeloid IRF8 levels may
lessen MDSC burden to boost responses to immunotherapies. One approach to achieve that translational goal
is to identify events that positively regulate IRF8 expression. Interestingly, recent studies have reported a novel
role for the Wnt/ß-catenin pathway in the regulation of MDSCs. As with IRF8, Wnt/ß-catenin appears to be a
negative regulator of MDSC generation. However, the molecular and functional relationship between these
two regulatory elements remain unknown. Thus, we hypothesize that IRF8 is regulated by Wnt/ß-catenin
signaling and that strategies which target this axis will enhance antitumor responses to ICIs. Importantly,
interventional agents that target Wnt/ß-catenin signaling are known. Our rationale to support this interaction is
based on data elsewhere that reveal putative Wnt/ß-catenin-associated transcription factors binding sites
within IRF8 and our preliminary data that show coordinated expression of both Wnt/ß-catenin and IRF8, which
declines in MDSCs relative to the controls. To test this hypothesis, we propose two aims in mouse models of
breast cancer: 1) to demonstrate that IRF8 expression is regulated by a Wnt/ß-catenin-dependent mechanism
to impact MDSCs; and 2) to test whether enhancing Wnt/ß-catenin signaling by genetic or pharmacologic
approaches enhance ICI responsiveness. Altogether, these studies have the potential to uncover a novel
Wnt/ß-catenin-IRF8 axis in MDSC biology and offer a therapeutic avenue for improving ICI efficacy.