Human leukocyte antigen class I-presented tumor antigens (HLA-I tumor ligands)

Tumor cell HLA class I ligands are short peptides, typically 8-11 amino acids in length, derived from intracellular proteins and presented on the cell surface by Human Leukocyte Antigen (HLA) class I molecules (Rock et al., 2016, Trends in Immunology). These ligands include neoantigens resulting from somatic mutations, cancer-testis antigens, and overexpressed self-antigens that distinguish malignant cells from healthy tissue. They serve as the primary targets for CD8+ cytotoxic T cells, which recognize the specific peptide-MHC complex via their T-cell receptors (TCRs). In oncology, these ligands are exploited for the development of TCR-engineered T-cell therapies (TCR-T), bispecific T-cell engagers known as ImmTACs, and cancer vaccines (Nathan et al., 2021, NEJM). For instance, the drug Tebentafusp specifically targets a gp100 peptide presented by HLA-A*02:01 to treat uveal melanoma. Effective targeting requires precise identification of the immunopeptidome and patient-specific HLA typing to ensure compatibility. A significant challenge in this field is the risk of lethal cross-reactivity if the targeted peptide sequence is shared with proteins in vital organs (Linette et al., 2013, Blood). Furthermore, tumors may develop resistance by downregulating HLA expression or through the loss of the specific target antigen.

Other names

Tumor-associated antigensNeoantigensMHC class I-restricted antigensTumor immunopeptidomePeptide-HLA complexespHLA

Recognition of specific peptide-HLA complexes by engineered T-cell receptors (TCRs) or TCR-mimetic bispecific molecules to induce directed T-cell mediated lysis of tumor cells.