Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells

• Published in: Frontiers in oncology Vol. 12; p. 739976
• Main Authors: Jiang, Wen, Li, Fanglin, Jiang, Yang, Li, Shengli, Liu, Xiaoli, Xu, Yaqi, Li, Binggen, Feng, Xiaoli, Zheng, Chengyun
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25.02.2022
• Subjects: adaptive immunotherapy; anti-tumor immunity; multiple myeloma; natural killer cells; Oncology; Tim-3; natural killer cells; adaptive immunotherapy; multiple myeloma; anti-tumor immunity; Tim-3
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.739976

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.