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Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression
Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794762/ https://www.ncbi.nlm.nih.gov/pubmed/29391449 http://dx.doi.org/10.1038/s41467-018-02912-x |
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author | Han, Chungyong Sim, Su-Jung Kim, Seon-Hee Singh, Rohit Hwang, Sunhee Kim, Yu I. Park, Sang H. Kim, Kwang H. Lee, Don G. Oh, Ho S. Lee, Sangeun Kim, Young H. Choi, Beom K. Kwon, Byoung S. |
author_facet | Han, Chungyong Sim, Su-Jung Kim, Seon-Hee Singh, Rohit Hwang, Sunhee Kim, Yu I. Park, Sang H. Kim, Kwang H. Lee, Don G. Oh, Ho S. Lee, Sangeun Kim, Young H. Choi, Beom K. Kwon, Byoung S. |
author_sort | Han, Chungyong |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells. |
format | Online Article Text |
id | pubmed-5794762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57947622018-02-05 Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression Han, Chungyong Sim, Su-Jung Kim, Seon-Hee Singh, Rohit Hwang, Sunhee Kim, Yu I. Park, Sang H. Kim, Kwang H. Lee, Don G. Oh, Ho S. Lee, Sangeun Kim, Young H. Choi, Beom K. Kwon, Byoung S. Nat Commun Article Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells. Nature Publishing Group UK 2018-02-01 /pmc/articles/PMC5794762/ /pubmed/29391449 http://dx.doi.org/10.1038/s41467-018-02912-x Text en © The Author(s) 2018 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Han, Chungyong Sim, Su-Jung Kim, Seon-Hee Singh, Rohit Hwang, Sunhee Kim, Yu I. Park, Sang H. Kim, Kwang H. Lee, Don G. Oh, Ho S. Lee, Sangeun Kim, Young H. Choi, Beom K. Kwon, Byoung S. Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression |
title | Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression |
title_full | Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression |
title_fullStr | Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression |
title_full_unstemmed | Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression |
title_short | Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression |
title_sort | desensitized chimeric antigen receptor t cells selectively recognize target cells with enhanced antigen expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794762/ https://www.ncbi.nlm.nih.gov/pubmed/29391449 http://dx.doi.org/10.1038/s41467-018-02912-x |
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