Programmed death-ligand 1 (PD-L1) peptide–Human Leukocyte Antigen (HLA) complex (PD-L1/HLA complex)

Peptide–HLA complexes derived from PD-L1 are molecular targets formed when the Programmed death-ligand 1 (PD-L1) protein is degraded by the proteasome and its resulting peptide fragments are presented on the cell surface by Human Leukocyte Antigen (HLA) molecules. While traditional checkpoint inhibitors target the surface-expressed PD-L1 protein to block its inhibitory interaction with PD-1, these peptide-MHC complexes allow for the direct targeting and elimination of PD-L1-expressing cells via T-cell receptor (TCR) recognition (Munir et al., 2013, Cancer Res). This approach is particularly effective for targeting tumor cells that use PD-L1 to evade immune detection, as it leverages the high specificity of TCRs or TCR-mimetic antibodies to induce direct cellular cytotoxicity (Shima et al., 2016, Oncol Rep). Therapeutic candidates such as ET190L1-T utilize engineered T cells to recognize these complexes, primarily in the context of the HLA-A*02:01 allele (Eureka Therapeutics, 2023). By targeting the presented peptide rather than the whole protein, this strategy expands the therapeutic window for PD-L1-positive malignancies and may overcome resistance to standard checkpoint blockade. However, the approach requires careful patient selection based on HLA type and carries risks of off-target reactivity if the targeted peptide sequence is shared by other proteins in healthy tissues.

Other names

PD-L1/MHC complexHLA-presented PD-L1 peptidesPD-L1-derived peptide-MHCCD274 peptide-HLA complexPD-L1 pMHC

Recognition of specific PD-L1-derived peptides (e.g., PD-L1 15-23) presented by HLA molecules (typically HLA-A*02:01) by T-cell receptors (TCRs) or TCR-mimetic antibodies, leading to the direct cytotoxic lysis of PD-L1-expressing cells and the induction of a pro-inflammatory tumor microenvironment.