Natural Killer cells (NK) are innate effector cells with a critical role in immunosurveillance against Multiple Myeloma (MM). However, during tumor progression, NK cell functions result significantly altered, and ultimately compromised in advanced disease. A better understanding of the mechanisms controlling NK cell versus MM effects could contribute to develop novel and combined therapeutic strategies in the treatment of this incurable hematologic malignancy.
Natural killer cell development and functional maturation are complex and multi-stage processes that occur predominantly in specialized niches of bone marrow (BM) through signals provided by particular cellular components, including bone marrow stromal cells (BMSCs). Several recent studies have shown functional abnormalities of MM patient-derived BMSCs indicating that they are active players in the pathophysiology of this disease. However, the possible impact of phenotypic and functional changes of these cells on NK cell differentiation during MM progression has not been studied yet. In addition, little and conflicting information is available on the role of BMSCs in the regulation of NK cell functions both in physiologic and pathologic conditions. To gain insight into this issue, we will investigate the possible role of MM-patients derived BMSCs on both NK cell development and functional properties.
Despite the significant advances in treatment, MM is still a fatal malignancy. Therefore, novel and alternative anti-MM therapeutic strategies are urgently needed. Particular attention has been given to the therapeutic potential of Natural Killer (NK) cells as important effectors of anti-myeloma immune response. Several lines of evidence describe the capability of NK cells to recognize and attack malignant plasma cells indicating a role for these lymphocytes in the control of MM development. NK cell number and activity correlate with the stage disease and result significantly reduced in advanced clinical stages, suggesting that the restoration of the quantitative and functional NK cell deficiencies is a suitable therapeutic opportunity for MM. An important and unexplored aspect is the possible impact of tumor microenvironment on NK cell development and differentiation in the BM. Both the tumor burden and a deeply altered BM microenvironment may prevent NK cells from becoming functionally mature.
Our interest is to understand how tumor microenvironment affects NK cell differentiation and function, focusing our attention on BM stromal cells (BMSCs). BMSCs are nonhematopoietic, multipotent progenitor cells, known to deeply affect NK cell development in physiological conditions. BMSCs can be genetically and functionally altered during MM progression but the possible impact of these changes on NK cell development and/or function remain unexplored. The comprehension of these complex mechanisms will be helpful to develop and improve NK cell-based therapies for MM. 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.