Tumor-antigen peptide-major histocompatibility complex (pMHC) (pMHC)

The target is the peptide-major histocompatibility complex (pMHC) displayed on the surface of tumor cells, which serves as the essential recognition unit for the adaptive immune system. This complex consists of a patient-specific MHC molecule (HLA in humans) presenting a peptide fragment derived from either a tumor-associated antigen (TAA) or a tumor-specific neoantigen (Schumacher & Schreiber, 2015, Science). TAAs are typically overexpressed or lineage-specific self-proteins, whereas neoantigens result from non-synonymous somatic mutations, making them unique to the tumor and less likely to trigger central tolerance (Tran et al., 2014, Science). Autologous tumor-infiltrating lymphocytes (TILs) recognize these pMHCs via their endogenous T-cell receptors (TCRs), leading to targeted tumor cell lysis (Rosenberg & Restifo, 2015, Science). Therapeutic strategies targeting this entity include TIL therapy, such as the FDA-approved lifileucel, and personalized neoantigen vaccines like mRNA-4157 (FDA, 2024; Moderna, 2023). Because the target is defined by the individual's HLA type and the tumor's unique mutational profile, it represents a highly personalized form of immunotherapy. Key challenges in targeting these complexes include the heterogeneity of antigen expression and the potential for tumor escape through the downregulation of MHC class I molecules (Yarchoan et al., 2017, NEJM).

Other names

Tumor-associated antigen (TAA)NeoantigenTumor-specific antigen (TSA)MHC-restricted tumor antigenNeoepitope-MHC complex

T-cell receptor-mediated tumor cell lysis via adoptive cell transfer of autologous tumor-infiltrating lymphocytes or active immunization against neoepitopes.