PROJECT SUMMARY
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.