Ricerc@Sapienza

Multiple Myeloma (MM) is a hematologic malignancy characterized by the accumulation of neoplastic plasma cells in the bone marrow microenvironment.
Progression of MM is supported by impairment of immunosurveillance due to CD8 T and Natural Killer (NK) cell alterations. In this regard, ligands able to trigger different activating receptors in these cells such as NKG2D, DNAM-1 and natural cytotoxicity receptors (NCRs) are expressed on the surface of MM cells and can induce potent anti-tumoral responses.
Despite recent advances in treatment, MM still remains an incurable disease; for this reason, it is important to find new molecules and pathways able to potentiate immune responses against this tumour.
Cholesterol is a major component of cell membranes and lipid rafts, where many cellular signalling pathways are activated. Experimental and clinical evidence has shown that survival of MM cells require more cholesterol than normal cells and the uptake of LDL-cholesterol suppresses MM cell apoptosis in culture (Tirado-Velez JM et al., Ann Hematol. 2012). Furthermore, hypocholesterolemia, due to increased LDL clearance and utilization of cholesterol by myeloma cells, is observed in patients with MM (Yavasoglu I. et al, Ann Hematol. 2008).
Liver-X-receptors (LXRs) are nuclear receptors involved in the regulation of gene expression in response to oxysterols. They are cholesterol sensors and regulate the transcription of gene products that control intracellular cholesterol and lipids homeostasis. They also play a role in inflammation and in immune system regulation and have direct anti-tumoral activities. In this regard, it has been observed that different LXR agonists can promote the inhibition of MM cells proliferation and their increased expression is associated to a good prognosis.
In this project, we will investigate the effect of LXR modulators on the expression of NK cell-activating ligands in MM cells and therefore their functional NK cell-regulatory activity.