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NUT carcinoma is caused by bromodomain-containing\n                      <jats:italic>NUTM1<\/jats:italic>\n                      fusion oncogenes, most commonly\n                      <jats:italic>BRD4::NUTM1<\/jats:italic>\n                      . BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called \u201cmegadomains\u201d with the overexpression of corresponding oncogenes, including\n                      <jats:italic>MYC<\/jats:italic>\n                      . We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single-labeled and double-labeled peptide standards, and gain\/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient-derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of\n                      <jats:italic>NUTM1<\/jats:italic>\n                      fusions (N=165). We created an \u03b1PRAME\n                      <jats:sub>425<\/jats:sub>\n                      T-cell receptor (TCR) \u00d7 SP34 \u03b1CD3 bispecific molecule modeled after brenetafusp, an \u03b1PRAME\n                      <jats:sub>425<\/jats:sub>\n                      TCR bispecific T-cell engager, as well as \u03b1PRAME\n                      <jats:sub>425<\/jats:sub>\n                      TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified\n                      <jats:italic>PRAME<\/jats:italic>\n                      as the most commonly expressed cancer\/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions (\n                      <jats:italic>BRD4::NUTM1<\/jats:italic>\n                      ,\n                      <jats:italic>BRD3::NUTM1<\/jats:italic>\n                      , and\n                      <jats:italic>NSD3::NUTM1<\/jats:italic>\n                      ). Additionally, 56% (43\/77) of NUT carcinoma tissue microarray samples stained positive for PRAME.\n                      <jats:italic>BRD4::NUTM1<\/jats:italic>\n                      expression in HEK 293T cells enhanced PRAME levels and\n                      <jats:italic>BRD4::NUTM1<\/jats:italic>\n                      knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived human leukocyte antigen (HLA) ligands (N=9) than all other cancer\/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01\/SLLQHLIGL (PRAME\n                      <jats:sub>425<\/jats:sub>\n                      ) epitope in 100% (4\/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (&gt;0.01\u2009fM) than HLA-A*02:01\/RLDQLLRHV (PRAME\n                      <jats:sub>312<\/jats:sub>\n                      ) or HLA-A*02:01\/YLHARLREL (PRAME\n                      <jats:sub>462<\/jats:sub>\n                      ). The \u03b1PRAME\n                      <jats:sub>425<\/jats:sub>\n                      TCR \u00d7 SP34 \u03b1CD3 bispecific molecule and \u03b1PRAME\n                      <jats:sub>425<\/jats:sub>\n                      TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against\n                      <jats:italic>PRAME<\/jats:italic>\n                      + NUT carcinoma cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>PRAME<\/jats:italic>\n                      is highly and frequently expressed in NUT carcinoma, and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrants clinical trials testing PRAME-targeted immunotherapies in this neglected patient population.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013539","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T14:30:16Z","timestamp":1770301816000},"page":"e013539","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Shared PRAME epitopes are T-cell targets in NUT carcinoma"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct05019716","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05372640","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05488548","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06112314","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03686124","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06743126","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05973487","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8821-4980","authenticated-orcid":false,"given":"Jeffrey L","family":"Jensen","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, The University of North Carolina at Chapel Hill Department of Medicine, Chapel Hill, North Carolina, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9858-2477","authenticated-orcid":false,"given":"Sara K","family":"Peterson","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6223-7324","authenticated-orcid":false,"given":"Maria J","family":"Sambade","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica R","family":"Alley","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1951-2949","authenticated-orcid":false,"given":"Shawn","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-7756","authenticated-orcid":false,"given":"Tomoaki","family":"Kinjo","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4605-2776","authenticated-orcid":false,"given":"Sarah N","family":"Bennett","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9399-5999","authenticated-orcid":false,"suffix":"II","given":"Steven P","family":"Vensko","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitra","family":"Shabrang","sequence":"additional","affiliation":[{"name":"Curriculum in Toxicology and Environmental Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan D","family":"Debetta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9579-379X","authenticated-orcid":false,"given":"Julie K","family":"Geyer","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2478-2081","authenticated-orcid":false,"given":"Brandon A","family":"Price","sequence":"additional","affiliation":[{"name":"Tempus AI Inc, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangok P","family":"Nickel","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8336-8000","authenticated-orcid":false,"given":"Randall J","family":"Kimple","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA"},{"name":"University of Wisconsin-Madison Carbone Cancer Center, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1836-4075","authenticated-orcid":false,"given":"Rishi S","family":"Kotecha","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children\u2019s Hospital, Perth, Western Australia, Australia"},{"name":"Leukemia Translational Research Laboratory, The Kids Research Institute Australia, Perth, Western Australia, Australia"},{"name":"Curtin Medical School, Curtin University, Perth, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E","family":"Herring","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J","family":"Davis","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Pediatrics, Division of Hematology-Oncology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-9418","authenticated-orcid":false,"given":"Jeremy R","family":"Wang","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A","family":"French","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Kuhlman","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2961-4447","authenticated-orcid":false,"given":"Jared M","family":"Weiss","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, The University of North Carolina at Chapel Hill Department of Medicine, Chapel Hill, North Carolina, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 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