Patient-specific tumor-associated peptide–HLA class I complex (pHLA-I)

Patient-specific tumor-associated peptide–HLA class I complexes are molecular assemblies on the surface of solid tumor cells that present intracellular antigens to the immune system (UniProt P04439). These complexes consist of a short peptide, often a neoantigen resulting from somatic mutations unique to an individual patient, non-covalently bound to a Human Leukocyte Antigen (HLA) class I molecule (Nature, 2017). Their primary biological function is to facilitate the recognition of "non-self" or "altered-self" cells by CD8+ cytotoxic T lymphocytes via the T-cell receptor (TCR) (Nature Reviews Cancer, 2021). In oncology, these complexes are exploited as highly specific therapeutic targets for personalized immunotherapies, including TCR-engineered T-cells (TCR-T) and personalized cancer vaccines (Nature Reviews Drug Discovery, 2021). Drugs targeting these complexes, such as Tebentafusp or personalized mRNA vaccines like mRNA-4157, are designed to bind the specific peptide-HLA combination with high affinity (PubMed PMID: 33654086). Because these targets are often restricted to specific HLA alleles (e.g., HLA-A*02:01) and unique peptide sequences, patient selection requires rigorous HLA typing and immunopeptidomic validation. A significant challenge in targeting these complexes is the potential for tumor immune escape through the downregulation of HLA expression or the loss of the presenting allele. Safety concerns include "on-target, off-tumor" toxicity if the targeted peptide is shared with healthy tissues, as well as systemic inflammatory responses like cytokine release syndrome.

Other names

pMHC-I complexNeoantigen-HLA complexTumor-specific antigen-MHC complexPeptide-MHC class I

T-cell receptor (TCR) mediated recognition and subsequent cytotoxic T-lymphocyte activation