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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,10]]},"abstract":"<jats:p>\n                    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 &gt; 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 &lt; 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\n                    <jats:italic>\u03b5<\/jats:italic>\n                    subunit (also known as a TRuC) and fully restored by exchanging the TCR\n                    <jats:italic>\u03b1<\/jats:italic>\n                    <jats:italic>\u03b2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2216352120","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T13:50:10Z","timestamp":1672840210000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":63,"title":["Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7251-8800","authenticated-orcid":false,"given":"Jake","family":"Burton","sequence":"first","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6624-7637","authenticated-orcid":false,"given":"Jes\u00fas A.","family":"Siller-Farf\u00e1n","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1979-8943","authenticated-orcid":false,"given":"Johannes","family":"Pettmann","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4282-6356","authenticated-orcid":false,"given":"Benjamin","family":"Salzer","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Kutuzov","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9902-6590","authenticated-orcid":false,"given":"P. 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