Inefficient CAR-proximal signaling blunts antigen sensitivity

Tools

Item Type:	Article
Title:	Inefficient CAR-proximal signaling blunts antigen sensitivity
Creators Name:	Gudipati, V., Rydzek, J., Doel-Perez, I., Gonçalves, V.D.R., Scharf, L., Königsberger, S., Lobner, E., Kunert, R., Einsele, H., Stockinger, H., Hudecek, M. and Huppa, J.B.
Abstract:	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.
Keywords:	Neoplasm Antigens, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Chimeric Antigen Receptors
Source:	Nature Immunology
ISSN:	1529-2908
Publisher:	Nature Publishing Group
Volume:	21
Number:	8
Page Range:	848-856
Date:	August 2020
Official Publication:	https://doi.org/10.1038/s41590-020-0719-0
PubMed:	View item in PubMed

Repository Staff Only: item control page