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Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor
Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated success in the treatment of hematological malignancies; however, its efficacy and applications in solid tumors remain limited. Immunosuppressive factors, particularly inhibitory checkpoint molecules, restrict CAR T cell activity i...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557556/ https://www.ncbi.nlm.nih.gov/pubmed/37808405 http://dx.doi.org/10.1080/2162402X.2023.2265703 |
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author | Zhao, Jingjing Dong, Jiebin Deng, Changwen Zhang, Qianjing Sun, Shicheng Li, Honggang Bai, Yun Deng, Hongkui |
author_facet | Zhao, Jingjing Dong, Jiebin Deng, Changwen Zhang, Qianjing Sun, Shicheng Li, Honggang Bai, Yun Deng, Hongkui |
author_sort | Zhao, Jingjing |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated success in the treatment of hematological malignancies; however, its efficacy and applications in solid tumors remain limited. Immunosuppressive factors, particularly inhibitory checkpoint molecules, restrict CAR T cell activity inside solid tumors. The modulation of checkpoint pathways has emerged as a promising approach to promote anti-tumor responses in CAR T cells. Programmed cell death protein 1 (PD1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two critical immune-checkpoint molecules that suppress anti-tumor activity in T cells. Simultaneous targeting of these two inhibitory molecules could be an efficient checkpoint modulation strategy. Here, we developed a PD1-TIGIT chimeric immune-checkpoint switch receptor (CISR) that enhances the efficacy of CAR T cell immunotherapy by reversing the inhibitory checkpoint signals of PD1/PDL1 and/or TIGIT/CD155. In addition to neutralizing PDL1 and CD155, this chimeric receptor is engineered with the transmembrane region and intracellular domain of CD28, thereby effectively enhancing T cell survival and tumor-targeting functions. Notably, under simultaneous stimulation of PDL1 and CD155, CISR-CAR T cells demonstrate superior performance in terms of cell survival, proliferation, cytokine release, and cytotoxicity in vitro, compared with conventional CAR T cells. Experiments utilizing both cell line- and patient-derived xenotransplantation tumor models showed that CISR-CAR T cells exhibit robust infiltration and anti-tumor efficiency in vivo. Our results highlight the potential for the CISR strategy to enhance T cell anti-tumor efficacy and provide an alternative approach for T cell-based immunotherapies. |
format | Online Article Text |
id | pubmed-10557556 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-105575562023-10-07 Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor Zhao, Jingjing Dong, Jiebin Deng, Changwen Zhang, Qianjing Sun, Shicheng Li, Honggang Bai, Yun Deng, Hongkui Oncoimmunology Brief Report Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated success in the treatment of hematological malignancies; however, its efficacy and applications in solid tumors remain limited. Immunosuppressive factors, particularly inhibitory checkpoint molecules, restrict CAR T cell activity inside solid tumors. The modulation of checkpoint pathways has emerged as a promising approach to promote anti-tumor responses in CAR T cells. Programmed cell death protein 1 (PD1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two critical immune-checkpoint molecules that suppress anti-tumor activity in T cells. Simultaneous targeting of these two inhibitory molecules could be an efficient checkpoint modulation strategy. Here, we developed a PD1-TIGIT chimeric immune-checkpoint switch receptor (CISR) that enhances the efficacy of CAR T cell immunotherapy by reversing the inhibitory checkpoint signals of PD1/PDL1 and/or TIGIT/CD155. In addition to neutralizing PDL1 and CD155, this chimeric receptor is engineered with the transmembrane region and intracellular domain of CD28, thereby effectively enhancing T cell survival and tumor-targeting functions. Notably, under simultaneous stimulation of PDL1 and CD155, CISR-CAR T cells demonstrate superior performance in terms of cell survival, proliferation, cytokine release, and cytotoxicity in vitro, compared with conventional CAR T cells. Experiments utilizing both cell line- and patient-derived xenotransplantation tumor models showed that CISR-CAR T cells exhibit robust infiltration and anti-tumor efficiency in vivo. Our results highlight the potential for the CISR strategy to enhance T cell anti-tumor efficacy and provide an alternative approach for T cell-based immunotherapies. Taylor & Francis 2023-10-05 /pmc/articles/PMC10557556/ /pubmed/37808405 http://dx.doi.org/10.1080/2162402X.2023.2265703 Text en © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. |
spellingShingle | Brief Report Zhao, Jingjing Dong, Jiebin Deng, Changwen Zhang, Qianjing Sun, Shicheng Li, Honggang Bai, Yun Deng, Hongkui Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor |
title | Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor |
title_full | Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor |
title_fullStr | Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor |
title_full_unstemmed | Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor |
title_short | Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor |
title_sort | enhancing t cell anti-tumor efficacy with a pd1-tigit chimeric immune-checkpoint switch receptor |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557556/ https://www.ncbi.nlm.nih.gov/pubmed/37808405 http://dx.doi.org/10.1080/2162402X.2023.2265703 |
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