PRAME Epitopes are T-Cell Immunovulnerabilities in BRD4::NUTM1 Initiated NUT Carcinoma

Abstract

NUT carcinoma ("NC") is a rare but highly lethal solid tumor without an effective standard of care. NC is caused by bromodomain-containing NUTM1 fusion genes, most commonly BRD4::NUTM1 . BRD4::NUTM1 recruits p300 to acetylate H3K27 forming "megadomains" with the overexpression of encapsulated oncogenes, most notably MYC . Akin to MYC , we hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer specific antigens that could be therapeutically actionable. Integrating genomics, immunopeptidomics, and computational biology approaches, we identified PRAME as the predominantly transcribed and HLA Class I-presented cancer/testis antigen in NC. Further, we show that a PRAME epitope-specific T-cell receptor ("TCR") x CD3 activator bispecific molecule modeled after brenetafusp has potent T-cell mediated activity against PRAME+ NC. Our results show that PRAME is often highly expressed in NC due to BRD4::NUTM1, and that BRD4::NUTM1 induced PRAME antigens are promising TCR targets for forthcoming clinical trials in NC.

Statement of significance: NC is one of the most aggressive solid tumors to afflict humans and is refractory to chemotherapy, T-cell checkpoint blockade, and targeted therapies. We show PRAME epitopes are promising targets for TCR-based therapeutics like brenetafusp in NC, adding to growing momentum for addressing challenging fusion malignancies with TCR therapeutics.