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Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effec...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307822/ https://www.ncbi.nlm.nih.gov/pubmed/35869100 http://dx.doi.org/10.1038/s41598-022-16616-2 |
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author | Li, Li Li, Qing Yan, Zi-Xun Sheng, Ling-Shuang Fu, Di Xu, Pengpeng Wang, Li Zhao, Wei-Li |
author_facet | Li, Li Li, Qing Yan, Zi-Xun Sheng, Ling-Shuang Fu, Di Xu, Pengpeng Wang, Li Zhao, Wei-Li |
author_sort | Li, Li |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effective resolution in clinical practice is still elusive. Inadequate persistence and subsequent loss of infused CAR-T cells are proposed major resistance mechanism associated with CAR-T cell treatment failure. Thus, we generated CAR-T cells armored with IL-7 to prolong the persistence of infused T-cells, particularly CD4 + T cells, and enhanced anti-tumor response. IL-7 increased CAR-T-cell persistence in vivo and contributed to the distinct T-cell cytotoxicity profile. Using mass cytometry (CyTOF), we further assessed the phenotypic and metabolic profiles of IL-7-secreting CAR-T cells, along with conventional CAR-T cells at the single-cell level. With in-depth analysis, we found that IL-7 maintained CAR-T cells in a less differentiated T-cell state, regulated distinct metabolic activity, and prevented CAR-T-cell exhaustion, which could be essential for CAR-T cells to maintain their metabolic fitness and anti-tumor response. Our findings thus provided clinical rationale to exploit IL-7 signaling for modulation and metabolic reprogramming of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy. |
format | Online Article Text |
id | pubmed-9307822 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93078222022-07-24 Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells Li, Li Li, Qing Yan, Zi-Xun Sheng, Ling-Shuang Fu, Di Xu, Pengpeng Wang, Li Zhao, Wei-Li Sci Rep Article Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effective resolution in clinical practice is still elusive. Inadequate persistence and subsequent loss of infused CAR-T cells are proposed major resistance mechanism associated with CAR-T cell treatment failure. Thus, we generated CAR-T cells armored with IL-7 to prolong the persistence of infused T-cells, particularly CD4 + T cells, and enhanced anti-tumor response. IL-7 increased CAR-T-cell persistence in vivo and contributed to the distinct T-cell cytotoxicity profile. Using mass cytometry (CyTOF), we further assessed the phenotypic and metabolic profiles of IL-7-secreting CAR-T cells, along with conventional CAR-T cells at the single-cell level. With in-depth analysis, we found that IL-7 maintained CAR-T cells in a less differentiated T-cell state, regulated distinct metabolic activity, and prevented CAR-T-cell exhaustion, which could be essential for CAR-T cells to maintain their metabolic fitness and anti-tumor response. Our findings thus provided clinical rationale to exploit IL-7 signaling for modulation and metabolic reprogramming of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy. Nature Publishing Group UK 2022-07-22 /pmc/articles/PMC9307822/ /pubmed/35869100 http://dx.doi.org/10.1038/s41598-022-16616-2 Text en © The Author(s) 2022 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/) . |
spellingShingle | Article Li, Li Li, Qing Yan, Zi-Xun Sheng, Ling-Shuang Fu, Di Xu, Pengpeng Wang, Li Zhao, Wei-Li Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells |
title | Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells |
title_full | Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells |
title_fullStr | Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells |
title_full_unstemmed | Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells |
title_short | Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells |
title_sort | transgenic expression of il-7 regulates car-t cell metabolism and enhances in vivo persistence against tumor cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307822/ https://www.ncbi.nlm.nih.gov/pubmed/35869100 http://dx.doi.org/10.1038/s41598-022-16616-2 |
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