Shared PRAME epitopes are T-cell targets in NUT carcinoma

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• NUT carcinoma is a rare, lethal cancer driven by NUTM1 fusion oncogenes like BRD4::NUTM1.
• BRD4::NUTM1 induces overexpression of oncogenes, potentially creating actionable cancer-specific antigens.

Purpose of the Study:

• To investigate the hypothesis that BRD4::NUTM1-induced transcriptional dysregulation generates therapeutically actionable cancer-specific antigens.
• To identify and validate PRAME as a potential therapeutic target in NUT carcinoma.

Main Methods:

• Integrated genomics, computational antigen prediction, and immunopeptidomics.
• Gain/loss-of-function experiments in cell lines, xenografts, and patient samples.
• Development and in vitro testing of PRAME-targeted T-cell receptor (TCR) bispecific molecules and T-cells.

Main Results:

• PRAME was the most frequently expressed cancer/testis antigen in NUT carcinoma samples with NUTM1 fusions.
• BRD4::NUTM1 expression increased PRAME levels, while its knockout decreased them.
• PRAME-derived HLA ligands were abundant, with the PRAME425 epitope detected in all tested HLA-A*02+ samples.
• PRAME-targeted TCR bispecifics and T-cells demonstrated potent cytotoxicity against PRAME+ NUT carcinoma cells.

Conclusions:

• PRAME is highly expressed in NUT carcinoma, with BRD4::NUTM1 contributing to its elevated levels.
• PRAME epitopes presented by HLA class I represent a novel therapeutic vulnerability.
• PRAME-targeted immunotherapies warrant clinical trials for NUT carcinoma patients.