Peptide–Human Leukocyte Antigen class I complex (pHLA-I)

The peptide–Human Leukocyte Antigen (HLA) class I complex on esophageal squamous cell carcinoma (ESCC) cells is a molecular assembly consisting of a tumor-derived peptide fragment bound to an HLA class I molecule, such as HLA-A*02:01 [1]. This complex is presented on the cell surface and acts as a critical ligand for CD8+ T-cell receptors (TCRs), enabling the immune system to recognize and destroy malignant cells [2]. In the context of ESCC, these complexes often present peptides from cancer-testis antigens like MAGE-A4 or NY-ESO-1, which are highly expressed in esophageal tumors but have limited expression in normal tissues, making them ideal therapeutic targets [3]. Therapeutic interventions, particularly TCR-engineered T-cell (TCR-T) therapies, are designed to bind specifically to these pHLA complexes with high affinity to trigger a potent cytotoxic response [4]. For example, afamitresgene autoleucel is a TCR-T therapy that targets the MAGE-A4 peptide in the context of HLA-A*02 [4]. Despite their promise, the efficacy of targeting these complexes can be hindered by tumor-mediated HLA downregulation or the loss of heterozygosity, which allows cancer cells to evade immune detection [5]. Furthermore, safety remains a concern due to the risk of cytokine release syndrome and potential off-target cross-reactivity with similar peptides in healthy tissues [6]. Sources: [1] UniProt (HLA-A, HLA-B, HLA-C entries). [2] NIH/National Cancer Institute (T-cell receptor therapy definitions). [3] "MAGE-A4 and NY-ESO-1 expression in esophageal squamous cell carcinoma," PubMed (PMID: 30254151). [4] "Afamitresgene Autoleucel for Advanced Synovial Sarcoma," The Lancet (relevant to ESCC trials like SPEARHEAD-1/2). [5] "HLA Class I Downregulation in Esophageal Cancer," Journal of Experimental & Clinical Cancer Research. [6] "Toxicity of TCR-T cell therapy," Nature Reviews Clinical Oncology.

Other names

pMHC-IPeptide-MHC class I complexTumor antigen-HLA complexHLA-peptide complexMHC class I-peptide complex

Engineered T-cell receptors (TCRs) or TCR-mimetic antibodies bind to the specific peptide-HLA complex on the tumor cell surface, leading to T-cell activation and subsequent lysis of the target cell.