Tumor antigen-derived peptide-MHC class I complex (pMHC-I)

The tumor antigen-derived peptide-MHC class I (pMHC-I) complex is a critical immunological assembly found on the surface of nucleated cells, including tumor cells and antigen-presenting cells (APCs) (Wikipedia, 2024). It consists of a polymorphic MHC class I heavy chain (HLA-A, B, or C in humans), a beta-2 microglobulin (β2M) light chain, and a short peptide (8-10 amino acids) derived from intracellular proteins (NIH, 2023). In the context of oncology, these peptides represent tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs), such as neoantigens or cancer-testis antigens, which are presented to CD8+ cytotoxic T lymphocytes (CTLs) (PubMed, 2021). Recognition of the pMHC-I complex by the T-cell receptor (TCR) is the primary signal for T-cell activation and subsequent lysis of the target cell (StatPearls, 2023). Therapeutic interventions targeting these complexes include TCR-engineered T cells (TCR-T), such as afamitresgene autoleucel (FDA, 2024), and bispecific T-cell engagers like tebentafusp (Nathan et al., 2021). However, the high specificity required to distinguish tumor-derived peptides from similar self-peptides on healthy tissues presents a significant safety challenge, as cross-reactivity can lead to severe off-target toxicities (Linette et al., 2013). Additionally, tumors often evade this recognition by downregulating components of the antigen-processing machinery, such as TAP transporters or B2M (NIH, 2024). Patient selection for these therapies typically requires screening for specific HLA genotypes and the presence of the target antigen (Precision Medicine Online, 2021). Overall, the pMHC-I complex represents a cornerstone of precision immunotherapy, enabling the immune system to identify and attack intracellular oncogenic drivers.

Other names

pMHC complexHLA-peptide complexTumor-associated antigen-MHC complexMHC-I-peptide complexAntigen-MHC class I complex

T-cell receptor (TCR) binding, CD8+ T-cell activation, and cytotoxic T-lymphocyte (CTL) mediated lysis of target cells