{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:59:58Z","timestamp":1793915998273,"version":"4.8.0"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"670","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,11,9]]},"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of\n                    <jats:italic>PRDM1<\/jats:italic>\n                    , encoding the BLIMP1 transcription factor, defined highly potent\n                    <jats:italic>TCF7<\/jats:italic>\n                    [encoding T cell factor 1 (TCF1)]\u2013expressing CD8\n                    <jats:sup>+<\/jats:sup>\n                    CAR T cells, whereas enrichment of\n                    <jats:italic>HAVCR2<\/jats:italic>\n                    [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]\u2013expressing CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells with elevated\n                    <jats:italic>PRDM1<\/jats:italic>\n                    was associated with poor outcomes.\n                    <jats:italic>PRDM1<\/jats:italic>\n                    knockout promoted\n                    <jats:italic>TCF7<\/jats:italic>\n                    -dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of\n                    <jats:italic>PRDM1<\/jats:italic>\n                    deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)\u2013driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of\n                    <jats:italic>NR4A3<\/jats:italic>\n                    and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of\n                    <jats:italic>PRDM1<\/jats:italic>\n                    and\n                    <jats:italic>NR4A3<\/jats:italic>\n                    skewed CAR T cell phenotypes away from TIM-3\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    and toward TCF1\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with\n                    <jats:italic>PRDM1<\/jats:italic>\n                    and\n                    <jats:italic>NR4A3<\/jats:italic>\n                    single knockout alone. These data underscore dual targeting of\n                    <jats:italic>PRDM1<\/jats:italic>\n                    and\n                    <jats:italic>NR4A3<\/jats:italic>\n                    as a promising approach to advance adoptive cell immuno-oncotherapy.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abn7336","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T13:58:03Z","timestamp":1668002283000},"source":"Crossref","is-referenced-by-count":140,"title":["BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3004-8083","authenticated-orcid":true,"given":"In-Young","family":"Jung","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\/0000-0002-8205-738X","authenticated-orcid":true,"given":"Vivek","family":"Narayan","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, 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