Tumor-associated self-antigen peptide–MHC class I complex (pMHC-I)

Tumor-associated self-antigen peptide–MHC class I complexes are molecular structures on the surface of cancer cells that present fragments of intracellular proteins to the immune system. These complexes consist of a peptide derived from a self-protein that is overexpressed or aberrantly expressed in tumors, such as cancer-testis antigens, bound to a Major Histocompatibility Complex (MHC) class I molecule (Yarchoan et al., 2017, Nature Reviews Cancer). Because these peptides are derived from internal cellular proteins, they allow the immune system to detect malignant transformations that are not visible to standard antibody-based therapies. Therapeutic strategies targeting these complexes include T-cell receptor (TCR) engineered T-cells and bispecific T-cell engagers that mimic TCR specificity. These therapies aim to trigger a potent and specific cytotoxic T-lymphocyte response against malignant cells while sparing healthy tissues. However, a significant challenge remains in ensuring that the targeted peptide-MHC complex is not present on essential healthy cells to avoid severe autoimmune-like toxicities (Morgan et al., 2013, JCO). Current clinical successes include treatments for uveal melanoma and various sarcomas using HLA-restricted recognition (Nathan et al., 2021, NEJM; D'Angelo et al., 2024, The Lancet). The specificity of these targets is determined by both the peptide sequence and the specific HLA allele presenting it, necessitating patient screening for both antigen expression and HLA type.

Other names

Tumor-associated antigen-MHC complexpMHC complexHLA-peptide complexMHC-restricted tumor antigenTAA-pMHCPeptide-HLA complex

Therapeutic agents targeting these complexes, such as TCR-engineered T-cells or bispecific T-cell engagers, utilize a T-cell receptor (TCR) or TCR-mimetic domain to specifically bind the peptide-MHC complex, thereby recruiting and activating cytotoxic T-lymphocytes to induce apoptosis in the target tumor cell (Nathan et al., 2021, NEJM; D'Angelo et al., 2024, The Lancet).