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Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans

“On-target off-tumor” toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid t...

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Autores principales: Wen, Lu, Huang, Yu, Peng, Ling, Zhao, Kaiping, Sun, Yan, Lin, Zhicai, Chen, Yuanyuan, Li, Zhong, Qian, Qijun, Tong, Fan, Zhang, Ruiguang, Dong, Xiaorong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428152/
https://www.ncbi.nlm.nih.gov/pubmed/36059490
http://dx.doi.org/10.3389/fimmu.2022.807915
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author Wen, Lu
Huang, Yu
Peng, Ling
Zhao, Kaiping
Sun, Yan
Lin, Zhicai
Chen, Yuanyuan
Li, Zhong
Qian, Qijun
Tong, Fan
Zhang, Ruiguang
Dong, Xiaorong
author_facet Wen, Lu
Huang, Yu
Peng, Ling
Zhao, Kaiping
Sun, Yan
Lin, Zhicai
Chen, Yuanyuan
Li, Zhong
Qian, Qijun
Tong, Fan
Zhang, Ruiguang
Dong, Xiaorong
author_sort Wen, Lu
collection PubMed
description “On-target off-tumor” toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid tumors, and would therefore appear to be a suitable antigen target. To understand the risk of toxicity to different organs on anti-mesothelin CAR T cell therapy, single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems were analyzed in this study, including the respiratory, cardiovascular, digestive, and urinary systems. According to scRNA-seq datasets, the organs were stratified into high or low risk based on the level of mesothelin expression. We report that the proportion of mesothelin-positive cells was 7.71%, 2.40% and 2.20% of myocardial cells, pulmonary cells and stomach cells, respectively, indicating that these organs could be at high risk of “on-target off-tumor” toxicity on anti-mesothelin CAR T cell therapy. By contrast, esophagus, ileum, liver, kidney and bladder exhibited low mesothelin expression (<1%). Therefore, these organs could be regarded as at low risk. Thus, the risk of toxicity to different organs and tissues in anti-mesothelin CAR T cell therapy may be predicted by these scRNA-seq data.
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spelling pubmed-94281522022-09-01 Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans Wen, Lu Huang, Yu Peng, Ling Zhao, Kaiping Sun, Yan Lin, Zhicai Chen, Yuanyuan Li, Zhong Qian, Qijun Tong, Fan Zhang, Ruiguang Dong, Xiaorong Front Immunol Immunology “On-target off-tumor” toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid tumors, and would therefore appear to be a suitable antigen target. To understand the risk of toxicity to different organs on anti-mesothelin CAR T cell therapy, single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems were analyzed in this study, including the respiratory, cardiovascular, digestive, and urinary systems. According to scRNA-seq datasets, the organs were stratified into high or low risk based on the level of mesothelin expression. We report that the proportion of mesothelin-positive cells was 7.71%, 2.40% and 2.20% of myocardial cells, pulmonary cells and stomach cells, respectively, indicating that these organs could be at high risk of “on-target off-tumor” toxicity on anti-mesothelin CAR T cell therapy. By contrast, esophagus, ileum, liver, kidney and bladder exhibited low mesothelin expression (<1%). Therefore, these organs could be regarded as at low risk. Thus, the risk of toxicity to different organs and tissues in anti-mesothelin CAR T cell therapy may be predicted by these scRNA-seq data. Frontiers Media S.A. 2022-08-17 /pmc/articles/PMC9428152/ /pubmed/36059490 http://dx.doi.org/10.3389/fimmu.2022.807915 Text en Copyright © 2022 Wen, Huang, Peng, Zhao, Sun, Lin, Chen, Li, Qian, Tong, Zhang and Dong 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
Wen, Lu
Huang, Yu
Peng, Ling
Zhao, Kaiping
Sun, Yan
Lin, Zhicai
Chen, Yuanyuan
Li, Zhong
Qian, Qijun
Tong, Fan
Zhang, Ruiguang
Dong, Xiaorong
Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans
title Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans
title_full Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans
title_fullStr Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans
title_full_unstemmed Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans
title_short Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans
title_sort single-cell rna-seq reveals the potential risk of anti-mesothelin car t cell therapy toxicity to different organs in humans
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428152/
https://www.ncbi.nlm.nih.gov/pubmed/36059490
http://dx.doi.org/10.3389/fimmu.2022.807915
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