Upstream open reading frames regulate proto-oncogene translation and encode HLA-presented immunogenic tumor antigens

ABSTRACT: Upstream open reading frames (uORFs) represent translational control elements within eukaryotic transcript leader sequences. Recent data showed that uORFs can encode for biologically active proteins and human leucocyte antigen (HLA)-presented peptides and suggest their potential role in cancer cell development and survival. However, it is so far unclear if uORF-encoded peptides could serve as tumor-associated antigen targets and thus also play a role in cancer immune surveillance. Combining mass spectrometry-based immunopeptidome analysis in primary tumor and healthy tissues and evaluation of proto-oncogene-associated uORF-mediated translational control we here identified a panel of HLA-presented tumor-associated uORF-derived antigens. These uORF-derived tumor antigens were further shown to induce multifunctional antigen-specific T cells, validating their suitability as antigen targets for T cell-based cancer immunotherapy. Our data further unravel the role of uORF-encoded peptides in malignant disease, suggesting uORF-derived tumor-associated antigens as targets for anti-cancer immune surveillance and immunotherapy development.

INSTRUMENT(S): LTQ Orbitrap, Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Juliane S. Walz  

PROVIDER: MSV000098383 | MassIVE | Mon Jun 30 04:44:00 BST 2025

SECONDARY ACCESSION(S): PXD025716

REPOSITORIES: MassIVE