Tumor antigen-major histocompatibility complex class I (pMHC-I)

The tumor peptide-major histocompatibility complex class I (pMHC-I) is a molecular assembly on the surface of cancer cells that presents intracellular protein fragments to the immune system (Nature Reviews Immunology, 2020). These complexes are formed when degraded tumor-associated antigens or neoantigens are loaded onto MHC class I molecules (HLA in humans) and transported to the cell membrane. Tumor-infiltrating lymphocyte T-cell receptors (TIL TCRs) are naturally occurring or engineered receptors that bind specifically to these pMHC-I targets, initiating a cytotoxic cascade that results in the destruction of the tumor cell (Nature Reviews Cancer, 2021). This interaction is the fundamental basis for several advanced immunotherapies, including TIL therapy (e.g., Lifileucel), where patient-derived T cells are expanded ex vivo, and TCR-T therapy (e.g., Afamitresgene autoleucel), where T cells are genetically modified to express a specific TCR (Lancet, 2024; FDA, 2024). Additionally, bispecific molecules like Tebentafusp utilize TCR domains to redirect T cells toward specific pMHC-I targets on uveal melanoma cells (NEJM, 2021). Because pMHC-I recognition is restricted by the patient's specific HLA type, these therapies are highly targeted but require precise patient selection based on both HLA genotype and the presence of the target antigen.

Other names

Tumor peptide-MHC complexHLA-peptide complexNeoantigen-MHC complexPeptide-MHC class I complexTIL TCR target

Recognition of specific tumor-derived peptides presented on MHC class I molecules by T-cell receptors (TCRs), leading to T-cell activation, cytokine release, and direct lysis of the tumor cell.