Non-canonical HLA-I-bound peptide (ncHLAp)

Cancer-restricted non-canonical HLA-I-bound cryptic peptides (ncHLAp) represent a novel class of tumor antigens derived from the translation of traditionally non-coding regions of the genome, often referred to as the dark genome. In pancreatic ductal adenocarcinoma (PDAC), a cancer typically characterized by a low mutational burden and resistance to conventional immunotherapies, these cryptic peptides are aberrantly expressed and presented by Human Leukocyte Antigen class I (HLA-I) molecules. Unlike traditional neoantigens that arise from somatic mutations, ncHLAp originate from alternative reading frames, untranslated regions (UTRs), and long non-coding RNAs (lncRNAs). Research has demonstrated that a significant portion of these peptides are highly specific to malignant cells and are shared across multiple patients, making them attractive targets for immunotherapy. Experimental approaches, such as T-cell receptor (TCR)-engineered T cells and cancer vaccines, have shown the ability to recognize these antigens and induce tumoricidal activity in preclinical models. Targeting ncHLAp offers a potential strategy to overcome the immunological cold nature of pancreatic cancer by expanding the pool of targetable surface markers beyond conventional protein-coding mutations.

Other names

Cryptic antigenNon-canonical antigenDark matter antigennuORF-derived peptideCancer-restricted cryptic antigenCancer-restricted non-canonical HLA-I-bound cryptic peptide