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Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals
T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the effi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957710/ https://www.ncbi.nlm.nih.gov/pubmed/33804441 http://dx.doi.org/10.3390/ijms22052476 |
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author | Fujiwara, Kento Kitaura, Masaki Tsunei, Ayaka Kusabuka, Hotaka Ogaki, Erika Okada, Naoki |
author_facet | Fujiwara, Kento Kitaura, Masaki Tsunei, Ayaka Kusabuka, Hotaka Ogaki, Erika Okada, Naoki |
author_sort | Fujiwara, Kento |
collection | PubMed |
description | T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the efficacy and toxicity of CAR-T cells, the relationship between CAR structure and CAR-T cell functions remains unclear. Here, we constructed second-generation CARs incorporating a signal transduction domain (STD) derived from CD3ζ and a 2nd STD derived from CD28, CD278, CD27, CD134, or CD137, and investigated the impact of the STD structure and signaling on CAR-T cell functions. Cytokine secretion of CAR-T cells was enhanced by 2nd STD signaling. T cells expressing CAR with CD278-STD or CD137-STD proliferated in an antigen-independent manner by their STD tonic signaling. CAR-T cells incorporating CD28-STD or CD278-STD between TMD and CD3ζ-STD showed higher cytotoxicity than first-generation CAR or second-generation CARs with other 2nd STDs. The potent cytotoxicity of these CAR-T cells was not affected by inhibiting the 2nd STD signals, but was eliminated by placing the STDs after the CD3ζ-STD. Our data highlighted that CAR activity was affected by STD structure as well as by 2nd STD signaling. |
format | Online Article Text |
id | pubmed-7957710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79577102021-03-16 Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals Fujiwara, Kento Kitaura, Masaki Tsunei, Ayaka Kusabuka, Hotaka Ogaki, Erika Okada, Naoki Int J Mol Sci Article T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the efficacy and toxicity of CAR-T cells, the relationship between CAR structure and CAR-T cell functions remains unclear. Here, we constructed second-generation CARs incorporating a signal transduction domain (STD) derived from CD3ζ and a 2nd STD derived from CD28, CD278, CD27, CD134, or CD137, and investigated the impact of the STD structure and signaling on CAR-T cell functions. Cytokine secretion of CAR-T cells was enhanced by 2nd STD signaling. T cells expressing CAR with CD278-STD or CD137-STD proliferated in an antigen-independent manner by their STD tonic signaling. CAR-T cells incorporating CD28-STD or CD278-STD between TMD and CD3ζ-STD showed higher cytotoxicity than first-generation CAR or second-generation CARs with other 2nd STDs. The potent cytotoxicity of these CAR-T cells was not affected by inhibiting the 2nd STD signals, but was eliminated by placing the STDs after the CD3ζ-STD. Our data highlighted that CAR activity was affected by STD structure as well as by 2nd STD signaling. MDPI 2021-03-01 /pmc/articles/PMC7957710/ /pubmed/33804441 http://dx.doi.org/10.3390/ijms22052476 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fujiwara, Kento Kitaura, Masaki Tsunei, Ayaka Kusabuka, Hotaka Ogaki, Erika Okada, Naoki Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals |
title | Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals |
title_full | Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals |
title_fullStr | Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals |
title_full_unstemmed | Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals |
title_short | Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals |
title_sort | structure of the signal transduction domain in second-generation car regulates the input efficiency of car signals |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957710/ https://www.ncbi.nlm.nih.gov/pubmed/33804441 http://dx.doi.org/10.3390/ijms22052476 |
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