Tumor-associated peptide–Major Histocompatibility Complex class I (pMHC-I)

Tumor-associated peptide–Major Histocompatibility Complex (MHC) class I complexes are essential molecular targets for cellular immunotherapy, representing the presentation of intracellular tumor-derived proteins to the immune system. These complexes consist of a short peptide fragment (typically 8–11 amino acids), derived from tumor-associated antigens (TAAs) or neoantigens, non-covalently bound within the groove of an MHC class I molecule (Human Leukocyte Antigen or HLA in humans) on the cell surface (Janeway's Immunobiology, 2017). Recognition of these complexes by the T-cell receptor (TCR) of CD8+ cytotoxic T cells is the fundamental mechanism for immune-mediated destruction of cancer cells. Unlike traditional monoclonal antibodies that target surface proteins, drugs targeting pMHC complexes can access the vast majority of the proteome that is intracellular, including transcription factors and metabolic enzymes (Yuan et al., 2021, Nature Reviews Drug Discovery). Current therapeutic strategies include TCR-engineered T-cell (TCR-T) therapies, such as Afamitresgene autoleucel, and bispecific T-cell engagers like Tebentafusp, which targets the gp100 peptide (Kim et al., 2022, NEJM). However, challenges such as HLA downregulation by tumors and the risk of lethal off-target cross-reactivity with similar peptides in healthy tissues remain significant hurdles in clinical development.

Other names

Tumor-specific antigen-MHC complexHLA-peptide complexNeoantigen-MHC complexCancer-testis antigen-MHC complexpMHC complex

Drugs targeting these complexes utilize engineered T-cell receptors (TCRs) or TCR-like antibodies to specifically recognize the peptide-HLA combination on the cell surface, subsequently recruiting or activating T-cells to induce perforin/granzyme-mediated lysis of the tumor cell (Nathan et al., 2021, NEJM; Yuan et al., 2021, Nature Reviews Drug Discovery).