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Tyrosine kinase signaling-independent MET-targeting with CAR-T cells
BACKGROUND: Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when ME...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544186/ https://www.ncbi.nlm.nih.gov/pubmed/37779207 http://dx.doi.org/10.1186/s12967-023-04521-9 |
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author | Qin, Anna Qin, Yuan Lee, Joseph Musket, Anna Ying, Mingyao Krenciute, Giedre Marincola, Francesco M. Yao, Zhi Q. Musich, Phillip R. Xie, Qian |
author_facet | Qin, Anna Qin, Yuan Lee, Joseph Musket, Anna Ying, Mingyao Krenciute, Giedre Marincola, Francesco M. Yao, Zhi Q. Musich, Phillip R. Xie, Qian |
author_sort | Qin, Anna |
collection | PubMed |
description | BACKGROUND: Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. METHODS: MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. RESULTS: MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. CONCLUSION: We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04521-9. |
format | Online Article Text |
id | pubmed-10544186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-105441862023-10-03 Tyrosine kinase signaling-independent MET-targeting with CAR-T cells Qin, Anna Qin, Yuan Lee, Joseph Musket, Anna Ying, Mingyao Krenciute, Giedre Marincola, Francesco M. Yao, Zhi Q. Musich, Phillip R. Xie, Qian J Transl Med Research BACKGROUND: Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. METHODS: MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. RESULTS: MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. CONCLUSION: We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04521-9. BioMed Central 2023-10-01 /pmc/articles/PMC10544186/ /pubmed/37779207 http://dx.doi.org/10.1186/s12967-023-04521-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 Qin, Anna Qin, Yuan Lee, Joseph Musket, Anna Ying, Mingyao Krenciute, Giedre Marincola, Francesco M. Yao, Zhi Q. Musich, Phillip R. Xie, Qian Tyrosine kinase signaling-independent MET-targeting with CAR-T cells |
title | Tyrosine kinase signaling-independent MET-targeting with CAR-T cells |
title_full | Tyrosine kinase signaling-independent MET-targeting with CAR-T cells |
title_fullStr | Tyrosine kinase signaling-independent MET-targeting with CAR-T cells |
title_full_unstemmed | Tyrosine kinase signaling-independent MET-targeting with CAR-T cells |
title_short | Tyrosine kinase signaling-independent MET-targeting with CAR-T cells |
title_sort | tyrosine kinase signaling-independent met-targeting with car-t cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544186/ https://www.ncbi.nlm.nih.gov/pubmed/37779207 http://dx.doi.org/10.1186/s12967-023-04521-9 |
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