Myeloid-derived Suppressor Cells: Characterization Of Their Role In Primary Myelofibrosis Pathogenesis For The Identification Of A New Therapeutic Target

Primary myelofibrosis (PMF) is a Philadelphia-negative chronic myeloproliferative disorder characterized by: clonal expansion of a malignant hematopoietic stem cell CD34+, bone marrow (BM) fibrosis, splenomegaly, extra-medullary hematopoiesis and an extensive neoangiogenesis in BM and spleen. Ninety-five % of patients have an acquired mutation of JAK2, CALR or MPL genes determining an activation of the JAK-STAT pathway in the myeloid lineage. Inflammation is currently thought to play a relevant role in PMF pathogenesis, as proven by high levels of inflammatory cytokines with prognostic significance and by a state of chronic oxidative stress with elevated reactive oxygen species (ROS).

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in patients with malignancies, sepsis or chronic inflammation. In steady state, MDSCs migrate from the BM to different peripheral organs, where they differentiate into macrophages, dendritic cells or granulocytes. Cytokines and chemokines that are produced in tumor microenvironment recruit immature myeloid cells in peripheral blood (PB), spleen, liver and lymphoid organs, prevent their differentiation (through the activation of STAT3 signalling pathway) and induce their activation into MDSCs. This cell population is conventionally divided in two subsets: polymorphonuclear (PMN)- and monocytic (M)-MDSCs. Besides, MDSCs have the strong ability to reduce cytotoxic functions of T/NK cells and the potential to differentiate into endothelial cells and incorporate in tumor endothelium, favoring tumor neoangiogenesis. Finally, Wang et al. found high levels of circulating MDSCs in patients with myeloproliferative neoplasms that were able to inhibit T cell proliferation.

These premises suggest that MDSCs could have a role in the pathogenesis of PMF by inhibiting some functions of immune cells, nurturing chronic inflammation that characterizes the disease and/or boosting the angiogenesis process.

A condition of chronic inflammation is commonly associated with an increase of MDSCs (number and activity) that contributes in maintaining and fueling inflammation through induction of oxidative stress by means of ROS production. In PMF patients, inflammation is thought to play a relevant role in the pathogenesis of the disease, as proven by high levels of inflammatory cytokines with prognostic significance and by a state of chronic oxidative stress. Few years ago, Wang et al. reported in a very limited number of patients with PMF an increase of the frequency of circulating MDSCs; however, they were not able, likely due to the small size of samples, to find any correlation between the number of MDSCs and both the genetic background and the disease phenotype.

The rationale of this project stems from the observations that in PMF all the premises that favor a role for MDSCs in the pathogenesis of the disease exist: a) a status of chronic inflammation, b) a variable degree of dysfunction of the immune system (that, together with activation of the JAK/STAT pathway due to driver mutations, could be responsible of disease progression), and c) extensive neoangiogenic processes.