Tumor-associated peptide–Human Leukocyte Antigen class I and II complex (pHLA complex)

Tumor-associated peptide–Human Leukocyte Antigen (HLA) class I and II complexes are the primary molecular targets for T-cell-mediated immunity against cancer. These complexes consist of a specific peptide fragment, derived from intracellular proteins such as neoantigens or overexpressed self-antigens, nestled within the binding groove of an HLA molecule on the cell surface (Nature Reviews Cancer, 2020). HLA class I complexes typically present endogenous peptides to CD8+ cytotoxic T cells, whereas HLA class II complexes primarily present peptides to CD4+ helper T cells (Janeway's Immunobiology, 2017). In malignant cells, the immunopeptidome displays unique or enriched peptides that distinguish them from healthy cells, providing a specific window for therapeutic intervention (Immatics, 2023). Modern immunotherapies, including TCR-engineered T cells (TCR-T) and bispecific T-cell engagers, are designed to recognize these specific pHLA targets with high affinity and specificity (Immunocore, 2022). By targeting these complexes, drugs can address intracellular oncogenic drivers that are inaccessible to traditional antibody-based therapies. However, the clinical success of targeting these complexes is often challenged by the heterogeneity of HLA expression and the risk of cross-reactivity with similar peptides found in vital organs (Journal for ImmunoTherapy of Cancer, 2021). Furthermore, tumors may evade treatment through the downregulation of HLA molecules or the loss of specific antigen presentation pathways.

Other names

MHC-peptide complexTumor-associated peptide (TUMAP)pMHCCancer immunopeptidomeAntigen-HLA complex

Therapeutic agents bind specifically to the peptide-HLA complex on the tumor cell surface, facilitating T-cell recognition and subsequent immune-mediated destruction of the malignant cell.