Inefficient CAR-proximal signaling blunts antigen sensitivity

Gudipati V, Rydzek J, Doel-Perez I, Goncalves VDR, Scharf L, Koenigsberger S, Lobner E, Kunert R, Einsele H, Stockinger H, Hudecek M, Huppa JB (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Nature Immunology Nature Research

Book Volume: 21

Pages Range: 848-856

Journal Issue: 8

DOI: 10.1038/s41590-020-0719-0

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.

Involved external institutions

Medizinische Universität Wien AT Austria (AT) Universitätsklinikum Würzburg DE Germany (DE) Universität für Bodenkultur Wien (BOKU) / University of Natural Resources and Life Sciences, Vienna AT Austria (AT)

How to cite

APA:

Gudipati, V., Rydzek, J., Doel-Perez, I., Goncalves, V.D.R., Scharf, L., Koenigsberger, S.,... Huppa, J.B. (2020). Inefficient CAR-proximal signaling blunts antigen sensitivity. Nature Immunology, 21(8), 848-856. https://doi.org/10.1038/s41590-020-0719-0

MLA:

Gudipati, Venugopal, et al. "Inefficient CAR-proximal signaling blunts antigen sensitivity." Nature Immunology 21.8 (2020): 848-856.

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