Tumor-associated peptide-Major Histocompatibility Complex (pMHC) (pMHC)

Tumor-associated peptide-Major Histocompatibility Complex (pMHC) molecules are the fundamental units of recognition for the adaptive cellular immune system in oncology (Nature Reviews Drug Discovery, 2021). These complexes are formed when intracellular proteins—including mutated neoantigens, overexpressed self-antigens, or cancer-testis antigens—are degraded by the proteasome and the resulting peptide fragments are loaded onto MHC (or HLA in humans) molecules for presentation on the cell surface (PubMed: 31434612). Tumor-infiltrating lymphocytes (TILs) possess T-cell receptors (TCRs) that specifically bind to these pMHC targets, initiating a signaling cascade that results in the targeted destruction of the cancer cell (Science, 2019). Therapeutic strategies leveraging this interaction include the expansion and re-infusion of TILs, such as Lifileucel (FDA, 2024), the engineering of T-cells with specific TCRs (TCR-T) like Afamitresgene autoleucel (FDA, 2024), and the development of bispecific TCR molecules like Tebentafusp (FDA, 2022). Because pMHCs allow the immune system to see the internal proteome of a cell, they offer a broader range of targets compared to traditional antibody-based therapies which are limited to surface proteins (Cell, 2020). However, the effectiveness of targeting pMHCs can be limited by tumor-mediated HLA downregulation and the risk of off-target toxicity if the targeted peptide is shared with essential healthy tissues (Journal of Clinical Investigation, 2013).

Other names

pHLApMHCTumor-specific peptide-MHCNeoantigen-MHC complexTumor-associated antigen-MHC complex

T-cell receptor mediated recognition and cytotoxic activation