{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:44:54Z","timestamp":1792719894014,"version":"4.5.0"},"reference-count":52,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"unspecified","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004337","name":"Roche","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,3,27]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Humanized mice are highly valuable models for the preclinical development of cancer immunotherapies. However, conventional models often fail to mount robust and trackable tumor antigen-specific (TA-specific) T-cell responses, which hinders the comprehensive evaluation of therapies that depend on this endogenous antitumor immunity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address this limitation, we generated a humanized mouse model by engrafting immunodeficient mice with human hematopoietic stem cells that were transduced with predefined T-cell receptor (TCR) specificities. This approach enables the de novo generation of na\u00efve, functional TA-specific T cells at adjustable frequencies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that transgene-bearing human thymocytes have a developmental advantage in the murine thymus, likely due to the early formation of the transgenic TCR and associated autonomous signaling. In tumor studies, the presence of these TA-specific T cells delayed tumor growth and promoted increased phenotypic diversity of intratumoral T cells, including the formation of PD-1\n                      <jats:sup>+<\/jats:sup>\n                      \/TCF1\n                      <jats:sup>+<\/jats:sup>\n                      precursor exhausted T cells, which were absent in control mice. We demonstrate the utility of this model in two distinct therapeutic contexts. First, we found that high baseline frequencies of TA-specific T cells blunted the efficacy of a T-cell bispecific antibody (TCB), suggesting that pre-existing exhaustion limits TCB activity. Furthermore, the model enabled the evaluation of costimulatory agonists (FAP-CD40 and FAP-4-1BBL), and demonstrated their dependence on this T-cell compartment for antitumor efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This adaptable and physiologically relevant model provides a platform to dissect the complex interplay between human tumors, immune cells, and immunotherapies and has the potential to significantly improve the translation of preclinical findings to the clinic.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013989","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T19:05:18Z","timestamp":1776279918000},"page":"e013989","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Precision modeling of tumor 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