Unconventional cancer antigen (UCA)

Unconventional cancer antigens (UCAs) are a class of tumor-specific peptides derived from non-canonical genomic sources, including introns, untranslated regions (UTRs), and non-coding RNAs (Nature, 2023). These antigens emerge from the 'dark matter' of the genome due to aberrant transcription and translation processes inherent to malignant cells, such as alternative splicing or out-of-frame translation (Science Immunology, 2021). UCAs are processed and presented on the cell surface via Major Histocompatibility Complex (MHC) molecules, where they can be recognized by CD8+ and CD4+ T cells (PubMed: 33053378). Unlike traditional neoantigens derived from exonic mutations, UCAs can be shared across different patients, offering significant potential for 'off-the-shelf' immunotherapies (Cell, 2019). They are currently being targeted by various therapeutic modalities, including mRNA-based vaccines and TCR-engineered T-cell therapies, to overcome the limitations of low mutational burden in certain 'cold' cancers (Journal of Clinical Investigation, 2022). Their discovery has significantly expanded the pool of targetable antigens, providing new avenues for precision oncology and immunotherapy.

Other names

Non-canonical cancer antigenCryptic antigenDark matter antigenNon-coding region-derived antigenOut-of-frame antigenHidden neoantigenNon-canonical ORF-derived peptide

Stimulation of antigen-specific T-cell responses through the presentation of non-canonical peptides on Major Histocompatibility Complex (MHC) molecules, leading to the recognition and lysis of tumor cells (Nature, 2023, doi:10.1038/s41586-023-06068-z).