Impact of the immunomodulatory effect of the combination HDACis/IMiDs in myelome multiple (MM).

Multiple Myeloma (MM) is a bone marrow (BM) malignancy. Since the introduction of immunomodulatory drugs (IMiDs) in MM treatment, the median survival of MM patients has increased from 3 to 5 years. The feature of this pharmaceutical class is to target the tumour-microenvironment and the immune system. Since February 2015, a histone deacetylase inhibitor (HDACi) has been approved by FDA in the treatment of MM. This pharmaceutical family is known for its direct cytotoxic effect on malignant cells, than its direct impact on the immune system; consequently the influence of the combination of both pharmaceutical classes is completely unknown. In this work we will investigate the immunotherapeutic action of the association IMiDs and/ or Gucocorticoide with HDACis on the immune system in MM. It seems clear that the impact of these drug combinations on the immune system have to be assessed as well as on NK cells and MM cell lines. We will evaluate in detail the exact drug
concentrations for the combination (IMiDs, Glucocorticoid, HDACis) to interfere positively on the tumour cells and the cells of the immune system.In addition, the impact of different drugs used in NK cell activation, in particularly on the expression of activating receptors and inhibitory receptors will be investigated and we will explore the expression of NK cell ligands in drug treated MM cells. We will evaluate Granules exocytosis and cytokine production (such as IFN-g) by drug-treated or untreated NK cells upon interaction with target cells. By immunoblotting we will perform the signaling pathways involved in NK cells granule exocytosis and activation,such as ERK, Vav, PI3K and NF-kB after treatment. MM cells also secrete inhibitory factors and express inhibitory molecules on their surface, thus the amount of soluble factors produced by drug-treated MM cells and the expression of inhibitory molecules will be evaluated.