Journal article
Shared PRAME epitopes are T-cell targets in NUT carcinoma
Journal for immunotherapy of cancer, Vol.14(2), p.e013539
02/05/2026
DOI: 10.1136/jitc-2025-013539
PMID: 41644270
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-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 NUTM1 fusions (N=165). We created an alpha PRAME(425) T-cell receptor (TCR) x SP34 alpha CD3 bispecific molecule modeled after brenetafusp, an alpha PRAME(425) TCR bispecific T-cell engager, as well as alpha PRAME(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 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(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 alpha PRAME(425) TCR x SP34 alpha CD3 bispecific molecule and alpha PRAME(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 warrants clinical trials testing PRAME-targeted immunotherapies in this neglected patient population.
Details
- Title: Subtitle
- Shared PRAME epitopes are T-cell targets in NUT carcinoma
- Creators
- Jeffrey L. Jensen - University of North Carolina at Chapel HillSara K. Peterson - University of North Carolina at Chapel HillMaria J. Sambade - University of North Carolina at Chapel HillJessica R. Alley - University of North Carolina at Chapel HillShawn Yu - University of North Carolina at Chapel HillTomoaki Kinjo - University of North Carolina at Chapel HillSarah N. Bennett - University of North Carolina at Chapel HillSteven P Vensko - UNC Lineberger Comprehensive Cancer CenterMitra Shabrang - University of North Carolina at Chapel HillJohnathan D. Debetta - Johns Hopkins UniversityJulie K. Geyer - University of North Carolina at Chapel HillBrandon A. Price - Tempus Labs (United States)Kwangok P. Nickel - University of Wisconsin–MadisonRandall J. Kimple - University of Wisconsin–MadisonRishi S. Kotecha - Translational Research InstituteLaura E. Herring - University of North Carolina at Chapel HillIan J. Davis - University of North Carolina at Chapel HillJeremy R. Wang - University of North Carolina at Chapel HillChristopher A. French - Harvard UniversityBrian Kuhlman - University of North Carolina at Chapel HillJared M. Weiss - University of North Carolina at Chapel HillAlex Rubinsteyn - University of North Carolina at Chapel HillBenjamin G. Vincent - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Journal for immunotherapy of cancer, Vol.14(2), p.e013539
- DOI
- 10.1136/jitc-2025-013539
- PMID
- 41644270
- ISSN
- 2051-1426
- eISSN
- 2051-1426
- Publisher
- Bmj Publishing Group
- Number of pages
- 15
- Grant note
- Postdoctoral Fellowship / PF-25-1412409-01-PFCDET, / American Cancer Society N/A / V Foundation for Cancer Research N/A / Max Vincze Foundation N/A / Victor Family Foundation P30 CA014520; P50CA278595; R01-CA276663; R35GM131923; R37 CA255330; T32CA285257; T32GM086330 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) N/A / Ben Brown Family P30 CA014520; P50CA278595; R37 CA255330 / UNC Department of Medicine ASCO Young Investigator Awards / New Rhein Foundat / Conquer Cancer Foundation Translational Team Science Award / #TTSA033P1 / School of Medicine, University of North Carolina at Chapel Hill Core Facilities CFAC Award / N/A / University of North Carolina Department of Medicine
- Language
- English
- Date published
- 02/05/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985178665102771
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