Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression
| Autor: | Young Ho Kim, Sunhee Hwang, Rohit Singh, Yu I. Kim, Don G. Lee, Beom K. Choi, Byoung S. Kwon, Kwang Hyun Kim, Su-Jung Sim, Sang Eun Lee, Seonhee Kim, Ho S. Oh, Chungyong Han, Sang H. Park |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Herpesvirus 4 Human T cell Science T-Lymphocytes Cell- and Tissue-Based Therapy Receptors Antigen T-Cell General Physics and Astronomy Mice Transgenic General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Downregulation and upregulation Antigen medicine Animals Humans Avidity Receptor lcsh:Science B-Lymphocytes Multidisciplinary biology Cell Death Chemistry Effector Antibodies Monoclonal General Chemistry HLA-DR Antigens Chimeric antigen receptor Recombinant Proteins Cell biology 030104 developmental biology medicine.anatomical_structure biology.protein lcsh:Q Female Antibody human activities HLA-DRB1 Chains |
| Zdroj: | Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2041-1723 |
| Popis: | 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. Engineered T cells with chimeric antigen receptor (CAR) are emerging as an effective cancer therapy. Here the authors show that CAR T cells recognizing self-MHC can be ‘tuned’ ex vivo via CAR downregulation and CAR T cell death to generate a CAR T pool specifically targeting tumor cells with high MHC expression. |
| Databáze: | OpenAIRE |
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