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Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors

Chimeric antigen receptor T cell therapy has become an important immunotherapeutic tool for overcoming cancers. However, the efficacy of CAR-T cell therapy in solid tumors is relatively poor due to the complexity of the tumor microenvironment and inhibitory immune checkpoints. TIGIT on the surface o...

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Autores principales: Yang, Fan, Zhang, Fan, Ji, Feng, Chen, Jiannan, Li, Jun, Chen, Zhengliang, Hu, Zhigang, Guo, Zhigang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287952/
https://www.ncbi.nlm.nih.gov/pubmed/37359558
http://dx.doi.org/10.3389/fimmu.2023.1175920
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author Yang, Fan
Zhang, Fan
Ji, Feng
Chen, Jiannan
Li, Jun
Chen, Zhengliang
Hu, Zhigang
Guo, Zhigang
author_facet Yang, Fan
Zhang, Fan
Ji, Feng
Chen, Jiannan
Li, Jun
Chen, Zhengliang
Hu, Zhigang
Guo, Zhigang
author_sort Yang, Fan
collection PubMed
description Chimeric antigen receptor T cell therapy has become an important immunotherapeutic tool for overcoming cancers. However, the efficacy of CAR-T cell therapy in solid tumors is relatively poor due to the complexity of the tumor microenvironment and inhibitory immune checkpoints. TIGIT on the surface of T cells acts as an immune checkpoint by binding to CD155 on the tumor cells’ surface, thereby inhibiting tumor cell killing. Blocking TIGIT/CD155 interactions is a promising approach in cancer immunotherapy. In this study, we generated anti-MLSN CAR-T cells in combination with anti-α-TIGIT for solid tumors treatment. The anti-α-TIGIT effectively enhanced the efficacy of anti-MLSN CAR-T cells on the killing of target cells in vitro. In addition, we genetically engineered anti-MSLN CAR-T cells with the capacity to constitutively produce TIGIT-blocking single-chain variable fragments. Our study demonstrated that blocking TIGIT significantly promoted cytokine release to augment the tumor-killing effect of MT CAR-T cells. Moreover, the self-delivery of TIGIT-blocking scFvs enhanced the infiltration and activation of MT CAR-T cells in the tumor microenvironments to achieve better tumor regression in vivo. These results suggest that blocking TIGIT effectively enhances the anti-tumor effect of CAR-T cells and suggest a promising strategy of combining CAR-T with immune checkpoints blockade in the treatment of solid tumors.
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spelling pubmed-102879522023-06-24 Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors Yang, Fan Zhang, Fan Ji, Feng Chen, Jiannan Li, Jun Chen, Zhengliang Hu, Zhigang Guo, Zhigang Front Immunol Immunology Chimeric antigen receptor T cell therapy has become an important immunotherapeutic tool for overcoming cancers. However, the efficacy of CAR-T cell therapy in solid tumors is relatively poor due to the complexity of the tumor microenvironment and inhibitory immune checkpoints. TIGIT on the surface of T cells acts as an immune checkpoint by binding to CD155 on the tumor cells’ surface, thereby inhibiting tumor cell killing. Blocking TIGIT/CD155 interactions is a promising approach in cancer immunotherapy. In this study, we generated anti-MLSN CAR-T cells in combination with anti-α-TIGIT for solid tumors treatment. The anti-α-TIGIT effectively enhanced the efficacy of anti-MLSN CAR-T cells on the killing of target cells in vitro. In addition, we genetically engineered anti-MSLN CAR-T cells with the capacity to constitutively produce TIGIT-blocking single-chain variable fragments. Our study demonstrated that blocking TIGIT significantly promoted cytokine release to augment the tumor-killing effect of MT CAR-T cells. Moreover, the self-delivery of TIGIT-blocking scFvs enhanced the infiltration and activation of MT CAR-T cells in the tumor microenvironments to achieve better tumor regression in vivo. These results suggest that blocking TIGIT effectively enhances the anti-tumor effect of CAR-T cells and suggest a promising strategy of combining CAR-T with immune checkpoints blockade in the treatment of solid tumors. Frontiers Media S.A. 2023-06-09 /pmc/articles/PMC10287952/ /pubmed/37359558 http://dx.doi.org/10.3389/fimmu.2023.1175920 Text en Copyright © 2023 Yang, Zhang, Ji, Chen, Li, Chen, Hu and Guo 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 Immunology
Yang, Fan
Zhang, Fan
Ji, Feng
Chen, Jiannan
Li, Jun
Chen, Zhengliang
Hu, Zhigang
Guo, Zhigang
Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors
title Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors
title_full Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors
title_fullStr Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors
title_full_unstemmed Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors
title_short Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors
title_sort self-delivery of tigit-blocking scfv enhances car-t immunotherapy in solid tumors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287952/
https://www.ncbi.nlm.nih.gov/pubmed/37359558
http://dx.doi.org/10.3389/fimmu.2023.1175920
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