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.
Although treatment strategies for multiple myeloma have changed substantially in the past decade, and the use of autologous hematopoietic stem cell transplantation and the introduction of new drugs, including immunomodulatory drugs (IMiDs), have significantly improved patients survival, most MM patients eventually relapse and become drug refractory. However, the mechanisms underlying resistance to IMiDs remain poorly understood. Among innovative strategies, improving NK cell responsiveness may be a promising therapeutic approach to treat MM. NK cells are a key components of innate immunity specialized to eliminate malignant cells via direct cytotoxicity and immune-regulatory cytokine production. NK cells contribute to cancer immune-editing, and are frequently deficient or dysfunctional in cancer patients. Novel immunotherapeutic strategies are oriented to the identification, isolation, expansion and administration of peculiar NK cell subsets endowed with multifunctional anti-tumor potential and a tropism versus tumor site.
This project aims at going insight the mechanisms of action of IMiDs and shedding light on NK-cell-mediated anti-myeloma activity. This study will improve our knowledge on immunomodulatory activities of these drugs in myeloma patients, by revealing whether and how their main cellular target, the protein CRBN, can regulate the function of NK cells. Moreover, it will be helpful to understand how modifications of expression/activities of this protein in distinct NK cell subsets may contribute to MM progression and development of drug resistance. Concomitantly, this study will provide a number of information about the complex biology of NK cells and their anti-myeloma activity, which are critical to design new approaches of cell adoptive transfer therapy.
All together the results of this research will lead to identification/use of different therapeutic strategies to fully exploit NK cell antitumor properties in the clinic. Finally, even if the focus of this project is multiple myeloma, if successful, the results could also be exploited and extended to other hematologic tumors and could therefore have a major health impacts.