Tumor-associated and neoantigen-derived peptides presented on Major Histocompatibility Complex (pMHC)

Tumor-associated and neoantigen-derived peptides presented on the Major Histocompatibility Complex (MHC) are the primary targets for T-cell-mediated cancer immunotherapy. These targets consist of short amino acid sequences (epitopes) derived from intracellular proteins that are processed by the proteasome and loaded onto MHC Class I or II molecules for surface display. Tumor-associated antigens (TAAs) are derived from proteins overexpressed in tumors but also present in normal tissues, while neoantigens arise from somatic mutations unique to the cancer cell, making them highly specific. The recognition of these peptide-MHC (pMHC) complexes by T-cell receptors (TCRs) is the fundamental step in immune surveillance and the induction of an anti-tumor response. Therapeutic interventions include TCR-engineered T cells (TCR-T), bispecific T-cell engagers (ImmTACs), and personalized vaccines that prime the immune system to recognize these specific signatures. However, challenges such as MHC downregulation by tumors and the requirement for specific HLA alleles in patients (HLA restriction) remain significant hurdles in the clinical application of these therapies.

Other names

Peptide-MHC complexTumor-specific antigen (TSA)Tumor-associated antigen (TAA)NeoantigenCancer-testis antigen (CTA)HLA-presented peptideImmunopeptidomeTumor neoepitope

Drugs targeting these complexes function through T-cell receptor (TCR) mediated recognition and activation, bispecific T-cell engagement (e.g., ImmTACs) to redirect T-cells to the tumor, vaccine-induced priming and expansion of antigen-specific T-cells, or adoptive transfer of TCR-engineered T-cells (TCR-T).