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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-8913933 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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