| Autor: |
Susana Minguet, Rubí Velasco Cárdenas, Simon Brandl, Emilia Schlaak, Annabelle Buschky, Timo Peters, Fabian Beier, Bryan Serrels, Sanaz Taromi, Katrin Raute, Simon Hauri, Matthias Gstaiger, Silke Lassman, Johannes Huppa, Melanie Boerries, Geoffroy Andrieux, Bertram Bengsch, Wolfgang Schamel |
| Rok vydání: |
2022 |
| DOI: |
10.21203/rs.3.rs-2378631/v1 |
| Popis: |
Current FDA-approved CAR T cells harbour the TCR-derived ζ chain as intracellular activation domain. The contribution of the other chains of the TCR complex, namely CD3δ, CD3ε, and CD3γ in a CAR format remains unknown. Here, we have systematically engineered novel CD3-based CARs. Unexpectedly, CARs containing CD3δ, CD3ε or CD3γ cytoplasmic tails outperformed conventional ζ CAR T cells in vivo. Transcriptomic and proteomic analysis revealed differences in activation potential, metabolism and stimulation-induced T cell dysfunctionality that mechanistically explain the enhanced anti-tumour performance. Using these CARs as minimalistic and synthetic surrogate TCRs, we have identified the phosphatase SHP-1 as a new interaction partner of CD3δ that binds the CD3δ-ITAM upon phosphorylation of its C-terminal tyrosine. SHP-1 attenuates and restrains activation signals and might thus prevent exhaustion and dysfunction. These new insights into T cell activation could promote the rational redesign of synthetic antigen receptors to improve cancer immunotherapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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