| Autor: |
Venugopal, Gudipati, Julian, Rydzek, Iago, Doel-Perez, Vasco Dos Reis, Gonçalves, Lydia, Scharf, Sebastian, Königsberger, Elisabeth, Lobner, Renate, Kunert, Hermann, Einsele, Hannes, Stockinger, Michael, Hudecek, Johannes B, Huppa |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
Nature immunology. 21(8) |
| ISSN: |
1529-2916 |
| Popis: |
Rational design of chimeric antigen receptors (CARs) with optimized anticancer performance mandates detailed knowledge of how CARs engage tumor antigens and how antigen engagement triggers activation. We analyzed CAR-mediated antigen recognition via quantitative, single-molecule, live-cell imaging and found the sensitivity of CAR T cells toward antigen approximately 1,000-times reduced as compared to T cell antigen-receptor-mediated recognition of nominal peptide-major histocompatibility complexes. While CARs outperformed T cell antigen receptors with regard to antigen binding within the immunological synapse, proximal signaling was significantly attenuated due to inefficient recruitment of the tyrosine-protein kinase ZAP-70 to ligated CARs and its reduced concomitant activation and subsequent release. Our study exposes signaling deficiencies of state-of-the-art CAR designs, which presently limit the efficacy of CAR T cell therapies to target tumors with diminished antigen expression. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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