{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T21:13:25Z","timestamp":1793654005600,"version":"4.5.1"},"reference-count":103,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"46","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,11,15]]},"abstract":"<jats:p>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting\n                    <jats:italic>TET2<\/jats:italic>\n                    in CAR T cells provides therapeutic benefit; however, TET2\u2019s role in exhausted T cell (T\n                    <jats:sub>EX<\/jats:sub>\n                    ) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell\u2013like T\n                    <jats:sub>EX<\/jats:sub>\n                    progenitors toward terminally differentiated and effector (T\n                    <jats:sub>EFF<\/jats:sub>\n                    )\u2013like T\n                    <jats:sub>EX<\/jats:sub>\n                    . TET2 also enforced a terminally differentiated state in the early bifurcation between T\n                    <jats:sub>EFF<\/jats:sub>\n                    and T\n                    <jats:sub>EX<\/jats:sub>\n                    , indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable\n                    <jats:italic>TET2-<\/jats:italic>\n                    targeted CAR T cells by disrupting\n                    <jats:italic>TET2<\/jats:italic>\n                    via knock-in of a safety switch alongside CAR knock-in at the\n                    <jats:italic>TRAC<\/jats:italic>\n                    locus.\n                    <jats:italic>TET2<\/jats:italic>\n                    -targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in T\n                    <jats:sub>EX<\/jats:sub>\n                    differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adp9371","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T14:00:02Z","timestamp":1731506402000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":42,"title":["TET2 regulates early and late transitions in exhausted CD8\n                    <sup>+<\/sup>\n                    T cell differentiation and limits CAR T cell function"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7337-3196","authenticated-orcid":true,"given":"Alexander J.","family":"Dimitri","sequence":"first","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1555-0713","authenticated-orcid":true,"given":"Amy E.","family":"Baxter","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department for Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-5083","authenticated-orcid":true,"given":"Gregory M.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6905-8268","authenticated-orcid":true,"given":"Caitlin R.","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman 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