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- W4313484994 abstract "Chimeric antigen receptors (CARs) can redirect T cells to target abnormal cells, but their activity is limited by a profound defect in antigen sensitivity, the source of which remains unclear. Here, we show that CARs have a > 100-fold lower antigen sensitivity compared to the T cell receptor (TCR) when antigen is presented on antigen-presenting cells (APCs) but nearly identical sensitivity when antigen is presented as purified protein. We next systematically measured the impact of engaging important T cell accessory receptors (CD2, LFA-1, CD28, CD27, and 4-1BB) on antigen sensitivity by adding their purified ligands. Unexpectedly, we found that engaging CD2 or LFA-1 improved the antigen sensitivity of the TCR by 125- and 22-fold, respectively, but improved CAR sensitivity by only < 5-fold. This differential effect of CD2 and LFA-1 engagement on the TCR vs. CAR was confirmed using APCs. We found that sensitivity to antigen can be partially restored by fusing the CAR variable domains to the TCR CD3 ε subunit (also known as a TRuC) and fully restored by exchanging the TCR α β variable domains for those of the CAR (also known as STAR or HIT). Importantly, these improvements in TRuC and STAR/HIT sensitivity can be predicted by their enhanced ability to exploit CD2 and LFA-1. These findings demonstrate that the CAR sensitivity defect is a result of their inefficient exploitation of accessory receptors and suggest approaches to increase sensitivity." @default.
- W4313484994 created "2023-01-06" @default.
- W4313484994 creator A5012406636 @default.
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- W4313484994 date "2023-01-04" @default.
- W4313484994 modified "2023-10-03" @default.
- W4313484994 title "Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors" @default.
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- W4313484994 doi "https://doi.org/10.1073/pnas.2216352120" @default.
- W4313484994 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36598945" @default.
- W4313484994 hasPublicationYear "2023" @default.
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