Abstract
Multiple myeloma (MM) is still an incurable plasma cell tumor. Natural killer (NK) cells are characterized by efficient anti-tumor activity, and their activity is one basis of cancer immunotherapeutic strategies. Tim-3, one of the immune checkpoint molecules, negatively regulates NK cell activity. To evaluate roles of the Tim-3 pathway blocking in the regulation of NK cell mediated- anti-MM activity in vitro and in vivo, anti-Tim-3 and/or anti-its ligand (HMGB1, CEACAM1 or Galetin-9) antibodies were applied respectively to block the Tim-3 pathway in the present study. Our results showed that Tim-3 was highly expressed on NK cells, in particular on in vitro expanded NK (exNK) cells. NK cells with Tim-3 blockade displayed a significantly higher degranulation and cytolytic activity against both human MM cell lines and primary MM cells, compared to the isotype control antibody-treated NK cells. The increased NK cell cytolytic activity by Tim-3 blocking was associated with up-regulation of cytotoxicity-related molecules, including perforin, granzyme B, TNF-α and IFN-γ. Ligand (HMGB1, CEACAM1 or Galetin-9) expression on MM cells was at different levels, and accordingly, the improvement in NK cell-mediated killing activity by different ligand blocking were also varying. Tim-3 blocking showed much more efficient enhancement of NK cell cytolytic activity than its ligand blockings. More importantly, exNK cells with Tim-3 blockade significantly inhibited MM tumor growth and prolonged the survival of MM-bearing NOD/SCID mice. Our results also showed that NK cells from peripheral blood and bone marrow of MM patients expressed much higher levels of Tim-3 than their counterparts from controls. Taken together, Tim-3 may be an important target molecule used for developing an antibody and/or NK cell based immunotherapeutic strategies for MM.
Highlights
Multiple myeloma (MM) is a malignant plasma cell tumor, characterized by an expansion of monoclonal plasma cells in the bone marrow and increased monoclonal immunoglobulin in the plasma
Our results presented in the current study show that Tim-3 blockage significantly enhances primary Natural killer (NK) cells and NK cell line mediated-killing of MM cells in vitro and in vivo, supporting the notion that Tim-3 may be an important target molecule used for developing an antibody and/or NK cell based immunotherapeutic strategies for MM
Antibody blocking experiments further confirmed that HMGB1 and CEACAM1 play more important roles in the system of NK cells killing MM cells
Summary
Multiple myeloma (MM) is a malignant plasma cell tumor, characterized by an expansion of monoclonal plasma cells in the bone marrow and increased monoclonal immunoglobulin in the plasma. MM accounts for about 13% of all hematological malignancies, and its incidence is increasing every year, and has become the second most common hematological tumor worldwide. In recent years, the application of new drugs such as proteasome inhibitors and immunomodulatory drugs have significantly improved the treatment efficacy and prolonged survival of MM patients (1, 2). The study of tumor microenvironmental immunity has revealed the role of immune cells in the occurrence and development of MM, which is of great significance for the development of new precise immune targets for the treatment of MM, and the understanding of the function of the immune system in MM
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