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| Item Type: | Article |
|---|---|
| Title: | Inefficient CAR-proximal signaling blunts antigen sensitivity |
| Creators: |
Gudipati, V.  ORCID: https://orcid.org/0000-0001-6647-0708, Rydzek, J., Doel-Perez, I. ORCID: https://orcid.org/0000-0003-0443-9718, Gonçalves, V.D.R. ORCID: https://orcid.org/0000-0001-9982-3346, Scharf, L. ORCID: https://orcid.org/0000-0002-1596-2208, Königsberger, S., Lobner, E. ORCID: https://orcid.org/0000-0002-5234-5524, Kunert, R. ORCID: https://orcid.org/0000-0002-3397-3621, Einsele, H., Stockinger, H. ORCID: https://orcid.org/0000-0001-6404-4430, Hudecek, M. ORCID: https://orcid.org/0000-0002-2280-2202 and Huppa, J.B. ORCID: https://orcid.org/0000-0003-2634-8198
|
| 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 |
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