Tumor antigen-peptide-major histocompatibility complex (pMHC)

Tumor antigen-peptide-major histocompatibility complexes (pMHCs) are the primary molecular targets for T-cell receptors (TCRs) on the surface of T cells, including tumor-infiltrating lymphocytes (TILs). These complexes consist of a short peptide fragment derived from intracellular tumor proteins—such as neoantigens or cancer-testis antigens—presented by MHC Class I or II molecules (Source: Nature Reviews Cancer, 2021). Research indicates that TILs expressing the PD-1 marker are highly enriched for TCRs that specifically recognize these tumor-specific pMHCs, making them a valuable source for identifying therapeutic TCR sequences (Source: Nature Medicine, 2016). Therapeutic interventions targeting these complexes include TCR-engineered T-cell (TCR-T) therapies and Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs), such as Tebentafusp (Source: FDA, 2022). These drugs function by redirecting the immune system to recognize and eliminate cells presenting the specific pMHC target. A critical challenge in targeting pMHCs is the risk of off-target toxicity, where the TCR may cross-react with similar peptides presented on vital healthy organs (Source: Blood, 2013). Consequently, rigorous screening for cross-reactivity is essential for the clinical development of drugs targeting these complexes. The identification of these targets often involves advanced sequencing and bioinformatic pipelines to match TIL-derived TCRs with their corresponding tumor-specific pMHCs.

Other names

Tumor pMHCHLA-peptide complexNeoantigen-MHC complexTumor-specific antigen-MHC complexTSA-MHC complex

Engineered T-cell receptors (TCRs) or TCR-bispecific molecules bind specifically to the peptide-MHC complex, triggering T-cell activation and subsequent lysis of the target tumor cell.