Noncoded cancer antigens

Aberrant translation in cancer cells can lead to the expression of peptides from genetic sequences outside of annotated open reading frames, such as 5′ and 3′ untranslated regions (UTRs), long noncoding RNAs, and alternative reading frames. These noncanonical peptides can then be presented by a complex called human leukocyte antigen class I (HLA-I) and recognized by T cells, but it is unclear whether they are cancer-specific and immunogenic. Now, Ely, Kulstad et al. have presented an immunopeptidomics study on organoids derived from patients with pancreatic ductal adenocarcinoma (PDAC), identifying such targetable, noncanonical or ‘cryptic’ peptides. They found that most cryptic peptides in the immunopeptidome of HLA-I-expressing patient-derived organoids (PDOs) were translated from the 5′ UTR. Examining the immunopeptidome from PDOs and healthy tissue showed that 30.2% of peptides were detected only in PDOs, and 29% of these cancer-specific peptides were shared by two or more patients with PDAC. The team followed up on 33 cancer-restricted cryptic peptides; 12 were immunogenic, priming CD8⁺ cytotoxic T lymphocytes from healthy donors and leading to the generation of antigen-specific T cells. Next, they used CRISPR–Cas9 to knock out endogenous T cell receptors (TCRs) and redirect the antigen specificity of TCRs in CD8⁺ T cells. The redirected T cells could recognize endogenous levels of the cryptic peptides in PDOs, kill PDOs, and significantly delay tumor growth in mice, showing that cryptic antigens could potentially be effective targets against solid pancreatic tumors. This high-resolution immunopeptidome profiling approach could potentially be applied to identify cryptic peptides in other solid tumors, and computational tools could be helpful to screen the deep immunopeptidomes for immunogenicity.

Original reference: Science 388, eadk3487 (2025)