The immunosuppressive role of the adipokine leptin in multiple myeloma

Multiple myeloma (MM) is characterized by an accumulation of monoclonal plasma cells in the bone marrow (BM) and progression of the disease is the result of a complex crosstalk between the different cell types present in this microenvironment. Although fatty deposits can occupy up to 70% of the BM cavity with aging, little attention has been given to the role of adipocytes in MM development. Moreover, immune cells can be influenced by adipokines, i.e. cytokines and hormones produced by white adipose tissue. The aim of this study is to investigate the role of the adipokine leptin and its receptor in supporting MM disease development, not only by a direct effect on MM cell proliferation but also by modulation of the protective tumor immunity. Our results show that leptin serum levels increase progressively during the course of the disease in the 5T33MM mouse model, an immunocompetent model for MM. Moreover, leptin was able to increase 5T33MM cell proliferation in vitro. We also detected a progressive upregulation of the leptin receptor on Natural Killer T cells (NKT) and different subsets of T cells during MM development. Functional analyses in vitro showed that leptin had inhibitory effects on the NKT cell function, immune cells which are important for anti-tumor immunity. Subsequently, a nanobody targeting the leptin receptor was tested in combination with an NKT stimulating agent, α-GalCer (α galactosylceramide), in order to examine the impact on MM disease in vivo. This combination prevented the occurrence of NKT cell anergy associated with the use of α-GalCer as a single agent and led to a complete inhibition of tumor development as measured by the M spike in the serum. Taken together, our preliminary data support the hypothesis that leptin could play an important function in MM pathology, not only on the MM cells themselves but also on the immune system. Pharmacologic manipulation of adipokines such as leptin in combination with immunotherapy could be an attractive novel strategy to target MM.