Translating the anti-myeloma activity of Natural Killer cells into clinical application.

Natural Killer cells (NK) are innate effector cells with a critical role in immunosurveillance against different kinds of cancer cells, including Multiple Myeloma (MM). However, the number and/or function of these lymphocytes are strongly reduced during MM progression and in advanced clinical stages. A better understanding of the mechanisms controlling both MM and NK cell biology have greatly contributed to develop novel and combined therapeutic strategies in the treatment of this incurable hematologic malignancy. These include approaches to reverse the immunosuppressive MM microenvironment or potentiate the natural or antibody-dependent cellular cytotoxicity (ADCC) of NK cells. Moreover, chemotherapeutic drugs or specific monoclonal antibodies (mAbs) can render cancer cells more susceptible to NK cell-mediated recognition and lysis; direct enhancement of NK cell function can be obtained by means of immunomodulatory drugs, cytokines and blocking mAbs targeting NK cell inhibitory receptors. Finally, adoptive transfer of ex-vivo expanded and genetically manipulated NK cells is also a promising therapeutic tool for MM. Here, we review current knowledge on complex mechanisms affecting NK cell activity during MM progression. We also discuss recent advances on innovative approaches aimed at boosting the functions of these cytotoxic innate lymphocytes. In particular, we focus our attention on recent preclinical and clinical studies addressing the therapeutic potential of different NK cell-based strategies for the management of MM.