A recurrent observation across various cancer types is that myelopoiesis is profoundly compromised. The resulting accumulation of immature myeloid cells, largely comprising cells termed myeloid-derived suppressor cells (MDSCs), often correlates with poor clinical outcomes due to their ability to suppress antitumor immunity and/or promote tumor angiogenesis. Thus, the overall goal of this proposal is to better understand how neoplasia cripples the normal process of myelopoiesis, leading to the generation of such MDSCs. From a translational or clinical perspective, understanding the molecular bases by which the neoplastic process cripples myelopoiesis has the potential to augment the efficacy of anticancer therapies that require a productive myeloid compartment. While efforts to eliminate MDSCs are strongly justified, the ability to do so has been plagued by a poor appreciation of the complexities of MDSC development. More specifically, a fundamental gap still remains as to how the neoplastic process is capable of generating a well-documented preferential expansion of the polymorphonuclear (PMN)-MDSC subset, which can account for up to 75% of aberrant myeloid accumulation at the tumor site. The elucidation of this knowledge is crucial to the improvement of therapies aimed at relieving tumor-driven immune suppression. Therefore, we believe it is critically important to define the precise developmental birthplace of the PMN-MDSC in order to identify the earliest possible cell type through which MDSC accumulation can be targeted therapeutically. Indeed, we now know that cells at the granulocyte progenitor (GP) stage of myelopoiesis taken from tumor-bearing hosts are already primed to produce PMN-MDSC, and that downregulation of the critical transcription factor IRF8 is necessary for this switch to occur. More recent data from our lab also strongly indicates that gene expression at the upstream GMP stage is similarly altered in tumor-bearing and IFN regulatory factor (IRF8)-/- hosts. Further analysis of these gene expression differences highlighted SLFN4, a gene which has recently been linked to myeloid cell development, as well as MDSC generation, as upregulated in both of these hosts. Since this strongly demonstrates that tumor-derived signals are being received upstream of the GP, we hypothesize that IRF8 inhibits PMN-MDSC development at the GMP stage through a SLFN4-dependent mechanism. Subsequent studies in this proposal will focus on further analysis of the IRF8-SLFN4 signaling axis, and its ability to control the switch between normal myelopoiesis and MDSC generation in the presence of cancer. Overall, defining which cell type represents the precise branching point for IRF8-mediated PMN-MDSC development has potentially significant conceptual and therapeutic merits. These novel insights could be exploited as new biomarkers for disease status, or targets that could reshape the myeloid phenotype in cancer.
Myelopoiesis is profoundly compromised in cancer patients, resulting in a loss of functional myeloid cells, and an expansion of immature myeloid cells known as myeloid-derived suppressor cells (MDSCs), which can suppress anti-tumor immunity. Because normal myeloid cells are essential for the induction of protective immunity, alterations in myelopoiesis could explain the failure to effectively control cancer progression. Therefore, understanding the molecular bases by which cancer cripples myelopoiesis will improve the efficacy of anticancer therapies that require a competent myeloid compartment to effectively engage and activate adaptive immune responses.
