Natural Killer (NK) cells are innate lymphocytes with a key role in anti-tumor immune response, due to their ability to recognize and lyse cancer cells. NK cells are a very heterogeneous population including distinct subsets endowed with different functions and homing properties. A number of evidences in myeloma patients strongly support the antitumor potential of NK cells in response to Immunomodulatory drugs (IMiDs). However, the molecular mechanisms underlying these effects and the role of the protein cereblon (CRBN), the cellular target of these drugs, have never been investigated in NK cells. Our preliminary results show that the ability to migrate and to form conjugates with target cells are significantly impaired in CRBN-depleted NK cells, suggesting the involvement of this protein in the regulation of NK cell functions.
Our proposal is aimed at identifying new tools to enhance NK cell therapeutic potential in MM. In Aim1 we will investigate the role of CRBN in pathways regulating NK cell activity and analyse possible functional alterations of this protein in NK cells from MM patients at different clinical stages; moreover, we will evaluate the impact of IMiDs on the activity of CRBN in MM patient-derived NK cells, focusing on the role of this protein in these lymphocytes in drug refractory and resistant patients. Since we have also preliminary findings revealing a marked change in the distribution of peculiar NK cell subsets in the bone marrow during MM progression, in Aim 2 we will study the possible contribution of CRBN in mediating the selective recruitment and functional properties of these subpopulations.
