Endogenous tumor antigen–peptide–MHC class I complex (pMHC-I)

The endogenous tumor antigen–peptide–MHC class I complex is a molecular assembly consisting of a tumor-derived peptide fragment bound within the groove of a Major Histocompatibility Complex (MHC) class I molecule on the surface of a cancer cell (Nature Reviews Drug Discovery, 2021). This complex serves as the primary signal for recognition by CD8+ T cells via their T-cell receptors (TCRs), facilitating the immune system's ability to identify and eliminate malignant cells (Janeway's Immunobiology, 9th Ed). In the context of immunotherapy, these complexes are highly specific targets because they allow for the targeting of intracellular proteins that are otherwise inaccessible to traditional antibody-based therapies (The Lancet, 2024). Drugs such as TCR-engineered T cells (TCR-T), like Afamitresgene autoleucel, and bispecific T-cell engagers, like Tebentafusp, are designed to bind these specific pMHC-I combinations with high affinity (FDA, 2022; FDA, 2024). By targeting these complexes, therapies can induce potent and selective destruction of tumor cells while sparing healthy cells that do not present the specific tumor-associated peptide. However, challenges include the requirement for specific HLA genotypes in patients and the potential for "off-target" toxicity if the targeted peptide sequence is shared by proteins in vital organs (Journal of Clinical Oncology, 2022).

Other names

Tumor-associated peptide-HLA complexpMHC complexAntigen-MHC class I complexHLA-peptide complexPeptide-major histocompatibility complex class I

Redirection of T-cell cytotoxicity through high-affinity binding of engineered T-cell receptors (TCRs) or TCR-like antibodies to specific peptide-MHC complexes on the tumor cell surface (Nature Reviews Drug Discovery, 2021).