Journal
NATURE IMMUNOLOGY
Volume 21, Issue 8, Pages 848-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-020-0719-0
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Funding
- Austrian Science Fund [W1224, P 25775-B2]
- Vienna Science and Technology Fund [LS14-031]
- Platform for Advanced Cellular Therapies
- Innovative Training Network EN-ACTI2NG (European Network on Anti-Cancer Immuno-Therapy Improvement by modification of CAR and TCR Interactions and Nanoscale Geometry) - European Commission
- German Cancer Aid (Max Eder Program) [70110313]
- German Research Foundation [324392634, TRR 221]
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Huppa and colleagues highlight signaling deficiencies in chimeric antigen receptor (CAR)-modified T cells that limit the efficacy of CAR T cell therapies to target tumors with diminished antigen expression. 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.
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