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

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. T...

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Autores principales: Jiang, Wen, Li, Fanglin, Jiang, Yang, Li, Shengli, Liu, Xiaoli, Xu, Yaqi, Li, Binggen, Feng, Xiaoli, Zheng, Chengyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913933/
https://www.ncbi.nlm.nih.gov/pubmed/35280800
http://dx.doi.org/10.3389/fonc.2022.739976
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author Jiang, Wen
Li, Fanglin
Jiang, Yang
Li, Shengli
Liu, Xiaoli
Xu, Yaqi
Li, Binggen
Feng, Xiaoli
Zheng, Chengyun
author_facet Jiang, Wen
Li, Fanglin
Jiang, Yang
Li, Shengli
Liu, Xiaoli
Xu, Yaqi
Li, Binggen
Feng, Xiaoli
Zheng, Chengyun
author_sort Jiang, Wen
collection PubMed
description 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.
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spelling pubmed-89139332022-03-12 Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells Jiang, Wen Li, Fanglin Jiang, Yang Li, Shengli Liu, Xiaoli Xu, Yaqi Li, Binggen Feng, Xiaoli Zheng, Chengyun Front Oncol Oncology 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. Frontiers Media S.A. 2022-02-25 /pmc/articles/PMC8913933/ /pubmed/35280800 http://dx.doi.org/10.3389/fonc.2022.739976 Text en Copyright © 2022 Jiang, Li, Jiang, Li, Liu, Xu, Li, Feng and Zheng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Jiang, Wen
Li, Fanglin
Jiang, Yang
Li, Shengli
Liu, Xiaoli
Xu, Yaqi
Li, Binggen
Feng, Xiaoli
Zheng, Chengyun
Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells
title Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells
title_full Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells
title_fullStr Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells
title_full_unstemmed Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells
title_short Tim-3 Blockade Elicits Potent Anti-Multiple Myeloma Immunity of Natural Killer Cells
title_sort tim-3 blockade elicits potent anti-multiple myeloma immunity of natural killer cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913933/
https://www.ncbi.nlm.nih.gov/pubmed/35280800
http://dx.doi.org/10.3389/fonc.2022.739976
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