Tumor peptide–Human Leukocyte Antigen complex (pHLA)

Tumor peptide–Human Leukocyte Antigen (pHLA) complexes are molecular assemblies on the surface of cancer cells that present intracellularly derived peptides to the immune system. These complexes are formed when proteins within the tumor cell are degraded by the proteasome into short peptides, which are then transported into the endoplasmic reticulum and loaded onto Major Histocompatibility Complex (MHC) molecules (UniProt). This mechanism allows T cells to monitor the internal state of the cell, identifying "non-self" or "altered-self" signals such as neoantigens from mutations or overexpressed tumor-associated antigens like MAGE-A4 or NY-ESO-1 (Nature Reviews Cancer). In oncology, pHLA complexes are highly specific therapeutic targets for T-cell receptor (TCR) engineered T-cells and bispecific T-cell engagers, such as Tebentafusp and Afamitresgene autoleucel (D'Angelo et al., 2024). Unlike traditional antibody targets that must be surface proteins, pHLA targeting expands the druggable proteome to include intracellular targets. However, clinical success is often limited by the requirement for specific HLA haplotypes (e.g., HLA-A*02:01) and the risk of off-target toxicity if the targeted peptide is shared by proteins in vital organs (PubMed). Additionally, tumors may evade these therapies by downregulating HLA expression or through the loss of heterozygosity in the HLA locus. These targets represent a cornerstone of personalized immunotherapy, requiring precise patient selection based on both antigen expression and HLA genotype.

Other names

pMHC complexPeptide-Major Histocompatibility ComplexTumor-associated antigen-HLA complexNeoantigen-HLA complexMHC-peptide complex

Engagement of T-cell receptors (TCRs) or TCR-mimetic molecules to recognize specific peptide-HLA combinations, triggering T-cell mediated cytotoxicity and cytokine release against the tumor cell.