Molecular mechanisms of tumor-induced myeloid-derived suppressor cell development
Waight, Jeremy D.
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Myelopoiesis is a tightly regulated process responsible for the development of a wide range of immune cell populations. Deregulation of this process at any stage results in the aberrant loss or accumulation of certain myeloid populations. Pathological conditions, such as cancer, exploit this phenomenon to facilitate tumor escape and progression. One of the most prominent cell populations to emerge from cancer-induced myelopoietic dysregulation is myeloid-derived suppressor cells (MDSC). These heterogeneous myeloid cells underline a large immunosuppressive network established during the neoplastic process, which functions to impair tumor-specific immune responses and promote tumor escape. Although much is known about the mechanisms by which MDSC promote tumor progression, far less is known about the transcriptional regimen that controls their development. Thus, a better understanding of the upstream molecular networks involved in the regulation or deregulation of myelopoiesis is paramount to the design of effective strategies to curtail the development of MDSC. The multifaceted transcription factor interferon regulatory factor-8 (IRF-8) is essential for myelopoietic homeostasis. In fact, IRF-8-deficiency leads to ingravescent myeloproliferative disease. Consistent with these observations, our research has revealed that IRF-8 expression is significantly downregulated in MDSC. We therefore investigated the role of IRF-8 in the maintenance of myelopoietic homeostasis and subsequent regulation of MDSC development. Using a model of IRF-8 deficiency (IRF-8 -/- mouse), we show that loss of IRF-8 alone results in the accumulation of MDSC. Complimentary in vivo studies, using multiple models of breast cancer, revealed that myeloid-intrinsic IRF-8 overexpression resulted in a significant constriction of MDSC accumulation. MDSC detention by enforced IRF-8 expression was sufficient to significantly slow tumor growth in several tumor models, suggesting the importance of this factor in the regulation of MDSC development. In addition, we have established a previously underappreciated role tumor-derived G-CSF in MDSC development. We observed that several tumor-derived factors (TDFs), including G-CSF, signal through a common STAT moiety to downregulate myeloid IRF-8 expression. This novel MDSC developmental axis was also present in other myeloid malignancies, such as CML. Our data highlight the importance of IRF-8 in the preservation of normal myelopoiesis and subsequent negative regulation of MDSC development. Collectively, our findings provide us with a better understanding of MDSC development which may have important implications for the design of anti-tumor therapies and the prognostic assessment of cancer patients.