Non-canonical tumor-associated antigen (Non-canonical TAA) (Non-canonical TAA)

Non-canonical tumor-associated antigens (TAAs) are a novel class of HLA-I bound peptides derived from genomic regions previously considered non-coding, such as introns, untranslated regions (UTRs), and alternative reading frames (Laumont et al., 2018). In cancer cells, the breakdown of normal transcriptional and translational fidelity leads to the expression of these "cryptic" sequences, which are then processed and presented on the cell surface by Human Leukocyte Antigen class I (HLA-I) molecules (Ouspenskaia et al., 2022). These peptides are highly cancer-restricted, offering a broader array of targets than traditional exonic neoantigens, particularly in tumors with low mutational burdens (Ruiz Cuevas et al., 2021). Therapeutic strategies targeting these antigens include personalized mRNA or viral-vectored vaccines, such as Gritstone bio's GRT-C901, and TCR-engineered T-cell therapies (Gritstone bio, 2024). By bypassing central tolerance—since these sequences are not typically expressed in healthy tissues—non-canonical TAAs provide a potent mechanism for inducing robust CD8+ T-cell mediated anti-tumor immunity. However, the clinical success of these targets depends on the precision of immunopeptidomic identification and the maintenance of HLA expression by the tumor to prevent immune escape.

Other names

Cancer-restricted non-canonical HLA-I bound peptidesCryptic antigensDark matter antigensNon-exonic HLA-I peptidesUnconventional tumor antigens

Induction of antigen-specific CD8+ T-cell responses through the recognition of non-canonical peptide-HLA class I complexes, leading to targeted tumor cell lysis.