Human leukocyte antigen class I molecules presenting cryptic peptides (HLA-I/cryptic peptide complex)

Human leukocyte antigen (HLA) class I molecules presenting cryptic peptides represent a novel class of therapeutic targets that expand the targetable immunopeptidome beyond traditional protein-coding sequences. Cryptic peptides are derived from non-canonical genomic regions such as introns, 5' and 3' untranslated regions (UTRs), and alternative reading frames that are typically not translated in healthy cells but become accessible due to dysregulated translation in cancer (Laumont et al., Nature Communications, 2018). These peptides are processed and presented on the cell surface by HLA class I molecules, making them visible to the immune system as tumor-specific antigens (Starck & Shastri, Expert Rev Clin Immunol, 2011). Because many of these "dark antigens" are highly specific to malignant cells and can be shared across different patients, they are ideal candidates for T-cell receptor (TCR)-based therapies and cancer vaccines (Enara Bio, 2023). Current therapeutic strategies involve using TCR-engineered T-cells or TCR-like antibodies to recognize these specific complexes and trigger a cytotoxic immune response (Gritstone Bio, 2024). However, the clinical application of these targets requires careful validation to avoid off-target toxicity and to address potential immune evasion through the loss of HLA expression (Erhard et al., Nature, 2018).

Other names

Non-canonical HLA-I peptidesDark antigensCryptic epitopesHidden tumor antigensOut-of-frame peptidesUnconventional MHC-I ligandsCryptic MHC-I antigens

Targeting via T-cell receptor (TCR) mimic antibodies, TCR-engineered T-cells (TCR-T), or CAR-T cells to induce targeted cell lysis upon recognition of the peptide-HLA complex.