{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:50:13Z","timestamp":1789753813357,"version":"4.0.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1<jats:sub>157-165<\/jats:sub> restricted to HLA-A*02:01. We compared the functions of the murine-derived TCR with human-derived TCRs and an affinity matured TCR, using <jats:italic>in vitro<\/jats:italic> co-culture and <jats:italic>in vivo<\/jats:italic> adoptive T cell transfer in tumor-bearing mice. Alanine scan, x-scan, LCL assay were employed to address the cross-reactivity of the NY-ESO-1<jats:sub>157-165<\/jats:sub> specific TCRs. We also used human tissue cDNA library and human primary cells to assess the safety of adoptive T cell therapies targeting NY-ESO-1 antigen in the clinic. One of the murine-derived human TCRs, TCR-ESO, exhibited higher functional avidity compared to human-derived NY-ESO-1<jats:sub>157-165<\/jats:sub> specific TCRs. TCR-ESO appeared to have similar efficiency in antigen recognition as an <jats:italic>in vitro<\/jats:italic> affinity-matured TCR, TCR 1G4-\u03b195LY, which was applied in clinical trials. TCR-ESO showed little cross-reactivity, in contrast to TCR 1G4-\u03b195LY. Our data indicate that highly effective TCRs against NY-ESO-1 are likely deleted in humans due to tolerance mechanisms, and that the TCR gene loci transgenic mice represent a reliable source to isolate effective and highly-specific TCRs for adoptive T cell therapies.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1524629","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T06:37:16Z","timestamp":1735022236000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Generation of effective and specific human TCRs against tumor\/testis antigen NY-ESO-1 in mice with humanized T cell recognition system"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiaojing Tina","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Leisegang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Gavvovidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Pollack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix K. 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