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A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects

BACKGROUND: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated ant...

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Autores principales: Wang, Wu, Wang, Xi, Yang, Wenli, Zhong, Kai, He, Na, Li, Xuexia, Pang, Yanyang, Lu, Zi, Liu, Aiqun, Lu, Xiaoling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444408/
https://www.ncbi.nlm.nih.gov/pubmed/34525966
http://dx.doi.org/10.1186/s12885-021-08732-5
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author Wang, Wu
Wang, Xi
Yang, Wenli
Zhong, Kai
He, Na
Li, Xuexia
Pang, Yanyang
Lu, Zi
Liu, Aiqun
Lu, Xiaoling
author_facet Wang, Wu
Wang, Xi
Yang, Wenli
Zhong, Kai
He, Na
Li, Xuexia
Pang, Yanyang
Lu, Zi
Liu, Aiqun
Lu, Xiaoling
author_sort Wang, Wu
collection PubMed
description BACKGROUND: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells,we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, wetested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. RESULTS: After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice. CONCLUSIONS: Ourfindings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential totreatmalignant tumors through in vivo adoptive therapy.
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spelling pubmed-84444082021-09-16 A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects Wang, Wu Wang, Xi Yang, Wenli Zhong, Kai He, Na Li, Xuexia Pang, Yanyang Lu, Zi Liu, Aiqun Lu, Xiaoling BMC Cancer Research BACKGROUND: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells,we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, wetested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. RESULTS: After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice. CONCLUSIONS: Ourfindings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential totreatmalignant tumors through in vivo adoptive therapy. BioMed Central 2021-09-15 /pmc/articles/PMC8444408/ /pubmed/34525966 http://dx.doi.org/10.1186/s12885-021-08732-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Wu
Wang, Xi
Yang, Wenli
Zhong, Kai
He, Na
Li, Xuexia
Pang, Yanyang
Lu, Zi
Liu, Aiqun
Lu, Xiaoling
A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
title A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
title_full A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
title_fullStr A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
title_full_unstemmed A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
title_short A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
title_sort ctla-4 blocking strategy based on nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444408/
https://www.ncbi.nlm.nih.gov/pubmed/34525966
http://dx.doi.org/10.1186/s12885-021-08732-5
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