Tumor antigen-Major Histocompatibility Complex (pMHC) (pMHC)

Tumor antigen-Major Histocompatibility Complex (pMHC) complexes are the primary molecular targets for T-cell-mediated immunity in cancer. These complexes consist of a short peptide fragment, derived from mutated (neoantigens) or overexpressed (tumor-associated antigens) intracellular proteins, bound within the groove of a Major Histocompatibility Complex (MHC) molecule on the cell surface (Janeway et al., 2001). T-cell receptors (TCRs) on tumor-infiltrating lymphocytes (TILs) specifically recognize these pMHCs, distinguishing malignant cells from healthy tissue (Abbas et al., 2021). This interaction is the basis for several advanced immunotherapies, including TIL therapy (e.g., lifileucel) and TCR-engineered T-cell (TCR-T) therapy (e.g., afamitresgene autoleucel) (FDA, 2024; Hong et al., 2023). Additionally, soluble TCR-based bispecifics like tebentafusp bridge T-cells to these pMHC targets, bypassing the need for endogenous TCR recognition (Nathan et al., 2022). The clinical utility of targeting pMHC is often constrained by the requirement for specific HLA genotypes in patients and the risk of off-target cross-reactivity with similar peptides in normal tissues (Linette et al., 2013).

Other names

Peptide-MHC complexpMHCTumor antigen-HLA complexNeoantigen-MHC complexAntigen-MHC complexTA-MHC

The mechanism involves the specific binding of a T-cell receptor (TCR) to the peptide-MHC complex, which initiates a signaling cascade through the CD3 complex and ZAP-70, leading to T-cell activation, proliferation, and the secretion of cytotoxic proteins like perforin and granzymes that induce tumor cell lysis (Janeway et al., 2001; Abbas et al., 2021).