Vitamin D Blocks CLL Cell-Mediated MDSC Induction

Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence amongst adults. CLL-associated immune defects promote tumor immune escape and antagonize immune-based therapies. We and others have reported the accumulation of so-called myeloid-derived suppressor cells (MDSCs) in CLL. Accumulation of immunosuppressive CD14⁺HLA-DR^low monocytic MDSCs is associated with advanced disease and poor prognosis. The mechanisms re-polarizing CLL-monocytes remain unknown. Here, we describe that CLL-cell-derived exosomes elicit a phenotypical and functional skewing of regular monocytes towards MDSCs. However, pre-treating CLL-cells with vitamin D led to a loss of the exosomes' MDSC-promoting capability. In fact, higher vitamin 25D serum concentrations were linked to lower levels of circulating MDSCs in CLL. A plethora of bioactive molecules including microRNAs (miRs) is shuttled in exosomes. MiR-155 is found abundantly in CLL-exosomes and using antagomir against miR-155 prevented exosomal MDSC-induction. Furthermore, exosomes from patients with lower vitamin D levels contained more miR-155 copies. Accordingly, vitamin D application reduced miR-155 production in CLL-cells Overall, we identified that exosomal miR-155 transfer promotes MDSCs in CLL. Vitamin D interferes with this interplay and could thereby represent a mean for enhancing immune responses in CLL.