Tumor antigen–Human Leukocyte Antigen complex (pHLA) (pHLA)

Tumor antigen–Human Leukocyte Antigen (HLA) complexes are the primary molecular signals used by the immune system to distinguish malignant cells from healthy ones (Rock et al., 2016, Protein Sci). These complexes consist of a short peptide fragment derived from intracellular proteins (the tumor antigen) bound within the groove of an HLA molecule on the cell surface. In the context of oncology, these antigens can be neoantigens resulting from mutations, overexpressed self-antigens, or cancer-testis antigens. Therapeutic strategies targeting these complexes include T-cell receptor (TCR) engineered T-cells and TCR-mimetic antibodies, which allow the immune system to recognize intracellular targets that are otherwise inaccessible to traditional antibody therapies (Nathan et al., 2021, N Engl J Med). By binding specifically to the pHLA complex, these drugs trigger T-cell mediated lysis of the cancer cell (D'Angelo et al., 2024, Lancet). However, the effectiveness of these therapies depends on the stable expression of the specific HLA allele and the presence of the target peptide, making HLA typing and antigen density critical factors for patient selection. Notable challenges include immune escape through HLA downregulation or loss of heterozygosity and the risk of off-target toxicity if the target peptide is shared with healthy tissues (McGranahan et al., 2017, Cell; Linette et al., 2013, Blood).

Other names

Peptide-MHC complexpMHCTumor-associated antigen-HLA complexNeoantigen-HLA complexpMHC class I complex

Redirection of T-cell cytotoxicity through specific recognition of peptide-HLA complexes by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies (Nathan et al., 2021, N Engl J Med; D'Angelo et al., 2024, Lancet).