Natural Killer Cells Activity Against Multiple Myeloma Cells Is Modulated by Osteoblast-Induced IL6 and IL-10 Production

Abstract

Natural killer (NK) cells are part of the innate arm of the immune system; as such NK cells can be activated rapidly to target virus-infected and tumor cells without prior sensitization. The human NK-92 cell line is among the most widely used NK cells in preclinical research studies and have also been approved for clinical applications. In this study we evaluated how osteoblasts (OSB), which are bone forming cells and a key cellular component of the bone marrow microenvironment, modulate the cytotoxic activity of NK-92 cells against the MM.1S multiple myeloma (MM) cell line. Previous studies have shown that OSB confer drug resistance in MM and other cancers that metastasize to the bone marrow. We report here that in the presence of OSB, NK-92 cells secreted less perforin and granzyme A, resulting in a concomitant decrease in MM.1S cells killing. The physical presence of OSB and NK-92 cells in the cultures also induced IL-6 and IL-10 production; two cytokines which are known to impair the NK cell immunity against multiple myeloma and other cancers. OSB supernatant also conferred cytoprotection to MM.1S, suggesting a dual mechanism by which OSB may modulate both NK and MM cells. As NK cells and their chimeric antigen receptor-modified versions become more widely used in the clinic, our results suggest that understanding the role of OSB as potential immunoregulators of the NK cell mediated cytotoxic response in the bone marrow tumor microenvironment may provide new opportunities for enhancing the activity of this potent immunotherapeutic approach. Funding Information: This study was supported by the National Institutes of Health, grant#: 1R33CA212806-01A1. Declaration of Interests: The authors declare that they have no conflict of interest.