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.
A number of cellular components of the immune system are implicated in antitumor immunity. Among these, Natural Killer cells are cytotoxic lymphocytes involved in the early defense against tumor cells, playing a key role in cancer immune-surveillance.
Our laboratory is pursuing the idea that NK cells may represent a promising therapeutic approach to treat MM; in particular, the modulation of the balance between activating and inhibitory NK cell signals and the sensitization of cancer cells to NK cell-mediated killing may significantly contribute to enhance anti-myeloma immune responses.
It has been proposed that the cell-intrinsic responses to stress (e.g. chemotherapy) are directly linked to cell-extrinsic responses, and this leads to a rapid NK cell-mediated surveillance and elimination of treated cancer cells. Engagement of activating receptors on NK cells and the increased expression of their ligands on MM cells is one of the mechanisms able to induce an anticancer response and represents an interesting therapeutic target for pharmacological modulation.
In our laboratory, we have shown that different pharmacological treatments used in therapy for MM, are able to regulate these ligands and to enhance NK cell-mediated killing against MM cells.
This research proposal is aimed at analyzing novel molecular mechanisms regulating NK cell responses against MM cells that could be useful to design or improve therapeutic strategies, combining low-dose chemotherapy with simultaneous NK cell activation protocols and/or infusion of NK cells.