Shared PRAME epitopes are T-cell targets in NUT carcinoma
Year: 2026
Type: article
Abstract: Background NUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing NUTM1 fusion oncogenes, most commonly BRD4::NUTM1 . BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called “megadomains” with the overexpression of corresponding oncogenes, including MYC . We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable. Methods We integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single- 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 NUTM1 fusions (N=165). We created an αPRAME 425 T-cell receptor x SP34 αCD3 bispecific molecule modeled after brenetafusp, an αPRAME 425 T-cell receptor bispecific T-cell engager, as well as αPRAME 425 TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells in vitro . Results We identified PRAME as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions ( BRD4::NUTM1 , BRD3::NUTM1 , and NSD3::NUTM1 ). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. BRD4::NUTM1 expression in HEK 293T cells enhanced PRAME levels and BRD4::NUTM1 knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived HLA ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME 425 ) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (>0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME 312 ) or HLA-A*02:01/YLHARLREL (PRAME 462 ). The αPRAME 425 T-cell receptor x SP34 αCD3 bispecific molecule and αPRAME 425 TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against PRAME + NUT carcinoma cells. Conclusions PRAME 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 warrant clinical trials testing PRAME targeted immunotherapies in this neglected patient population. What is already known on this topic NUT carcinoma is a devastating malignancy that is recalcitrant to cytotoxic chemotherapy, T-cell checkpoint blockade, and targeted therapies in the form of bromodomain inhibitors. What this study adds NUT carcinoma tumors are high in the cancer/testis gene PRAME . The oncogene most commonly causing NUT carcinoma, BRD4::NUTM1 , contributes to these high levels. NUT carcinoma cells present PRAME epitopes on HLA Class I molecules and are susceptible to PRAME-directed, T-cell mediated cytotoxicity. How this study might affect research, practice or policy Our results argue for phase I/II clinical trials testing PRAME immunotherapies like brenetafusp or anzutresgene autoleucel in PRAME + NUT carcinoma patients. Graphical Abstract
Authors: Jeffrey L. Jensen, Sara K. Peterson, Maria Sambade, Jessica R. Alley, Shawn Yu, Tomoaki Kinjo, Sarah N. Bennett, Steven P. Vensko, Mitra Shabrang, Johnathan D. DeBetta, Julie K. Geyer, Brandon A. Price, Kwangok P. Nickel, Randall J. Kimple, Rishi S. Kotecha, Laura E. Herring, Ian J. Davis, Jeremy R. Wang, Christopher A. French, Brian Kuhlman, Jared Weiss, Alex Rubinsteyn, Benjamin G. Vincent
Institutions: University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Johns Hopkins University, University of Wisconsin–Madison, University of Wisconsin Carbone Cancer Center, The Kids Research Institute Australia, The University of Western Australia, Curtin University, Princess Margaret Hospital for Children, Perth Children's Hospital, Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
Funders: Deanship of Scientific Research, King Khalid University, Human Resource Development Centre, Council of Scientific And Industrial Research, Howard Hughes Medical Institute, American Diabetes Association, American Cancer Society, Bill and Melinda Gates Foundation, Conquer Cancer Foundation, V Foundation for Cancer Research, Cervical Spine Research Society, Pfizer, Compagnia di San Paolo, Universitetet i Tromsø, Kræftens Bekæmpelse, Deutsches Krebsforschungszentrum, Centre International de Recherche sur le Cancer, Fondation Brain Canada, Weston Brain Institute, World Cancer Research Fund International, UK Research and Innovation, Stanford Diabetes Research Center, Danish Cancer Society Research Center, International Progressive MS Alliance, AstraZeneca España, Cancer Research UK, National Institute for Health and Care Research, Multiple Sclerosis Society, Imperial College London, University of Oxford, Deutsche Forschungsgemeinschaft, Fondation Leducq, Institut National de la Santé et de la Recherche Médicale, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, ZonMw, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Bundesministerium für Bildung und Forschung, Cancerfonden, China Postdoctoral Science Foundation, Fredrik och Ingrid Thurings Stiftelse, Ministero della Salute, Natural Science Foundation of Fujian Province, Hjärnfonden, Karolinska Institutet, Qatar University, Vetenskapsrådet, Sichuan University, Natural Science Foundation of Heilongjiang Province, Deutsche Krebshilfe, Natural Science Foundation of Shandong Province, Sveriges Läkarförbund, Svenska Läkaresällskapet, Tanta University, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Læge Agnethe Løvgreens Legat, Jawaharlal Institute Of Postgraduate Medical Education and Research, Huzhou Municipal Science and Technology Bureau, Aage og Johanne Louis-Hansens Fond, State Key Laboratory of Robotics and System, Army Medical University, Lembaga Pengelola Dana Pendidikan, Urmia University of Medical Sciences, Ministry of Health of the Republic of Indonesia, King Salman Center for Disability Research, Guangzhou Municipal Science and Technology Bureau, Fonds de recherche du Québec, National Institutes of Health, Applied Basic Research Foundation of Yunnan Province, Agricultural Research Service, Horizon 2020 Framework Programme, Qatar National Library, Canadian Institutes of Health Research, Engineering and Physical Sciences Research Council, Economic and Social Research Council, World Cancer Research Fund, National Health and Medical Research Council, Korea National Institute of Health, Instituto de Salud Carlos III, College of Medicine and Health Sciences, United Arab Emirates University, European Regional Development Fund, Fundamental Research Funds for the Central Universities, Science and Technology Planning Project of Guangdong Province, NIHR Imperial Biomedical Research Centre, Clarendon Fund, Natural Science Basic Research Program of Shaanxi Province, Basic and Applied Basic Research Foundation of Guangdong Province, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Biomedical Imaging and Bioengineering, School of Medicine, University of North Carolina at Chapel Hill, Department of Epidemiology and Biostatistics, University of California, San Francisco, University of Tennessee - Oak Ridge Innovation Institute
Awards: G1204613198, G42679306, G4319453063, G445467929, G8660341340, Gvl mHA Specific T Cell Responses Prevent AML Relapse Following Allogeneic Stem Cell Transplantation., Improving the translational value of head and neck cancer patient-in-mouse models, Developmental control of chromatin states in cancer, UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program, UNC Immunotherapy Training Grant (IM-TAG), Pre- and Postdoctoral Training in Toxicology
OpenAlex ID: W7128075992