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/?-catenin pathway in the regulation of MDSCs. As with IRF8, Wnt/?-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/?-catenin signaling and that strategies which target this axis will enhance antitumor responses to ICIs. Importantly, interventional agents that target Wnt/?-catenin signaling are known. Our rationale to support this interaction is based on data elsewhere that reveal putative Wnt/?-catenin-associated transcription factors binding sites within IRF8 and our preliminary data that show coordinated expression of both Wnt/?-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/?-catenin-dependent mechanism to impact MDSCs; and 2) to test whether enhancing Wnt/?-catenin signaling by genetic or pharmacologic approaches enhance ICI responsiveness. Altogether, these studies have the potential to uncover a novel Wnt/?-catenin-IRF8 axis in MDSC biology and offer a therapeutic avenue for improving ICI efficacy.
Myeloid-derived suppressor cells (MDSCs) are population of immune cells that arise in neoplastic disease and suppress antitumor responses in both preclinical cancer models and patients across diverse tumor types, including breast cancer. A major gap exists in our understanding of the pathways and cues that govern their development and function, which is critical for the identification of new molecular targets for therapeutic intervention. This proposal seeks to define a novel signaling axis in the regulation of MDSCs in breast cancer, which not only will advance our knowledge of MDSC biology, but also will offer unique insights into a previously unrecognized molecular network for mitigating the effects of MDSCs as negative regulators of immune- targeted therapies.
