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

Tumor cell peptide–Major Histocompatibility Complex (pMHC) complexes are the fundamental units of recognition for the adaptive cellular immune system in oncology (Restifo et al., Nature Reviews Cancer, 2012). These complexes are formed when intracellular proteins, including mutated neoantigens or overexpressed tumor-associated antigens, are processed into short peptides and loaded onto MHC molecules (Human Leukocyte Antigens or HLA in humans) for presentation on the cell surface (Abbas et al., Cellular and Molecular Immunology, 2021). Patient-derived Tumor-Infiltrating Lymphocytes (TILs) utilize their endogenous T-cell receptors (TCRs) to bind these specific pMHC targets, initiating a cascade that results in the destruction of the tumor cell. This interaction is the basis for several advanced immunotherapies, including TIL therapy (e.g., Lifileucel), where naturally occurring T cells are expanded ex vivo, and TCR-T therapy (e.g., Afamitresgene autoleucel), where T cells are engineered to express a specific TCR (FDA, 2024). Because pMHC complexes allow the immune system to see the internal proteome of a cell, they represent a critical class of targets for treating solid tumors that may lack traditional surface-bound antigens. However, the effectiveness of targeting these complexes can be limited by the heterogeneity of antigen expression and the potential for the tumor to downregulate MHC molecules to evade detection (Garrido et al., Cancer Immunology, Immunotherapy, 2017).

Other names

pMHC complexHLA-peptide complexTumor-specific antigen-MHC complexNeoantigen-HLA complexTumor-associated antigen-HLA complex

The mechanism involves the high-affinity binding of a T-cell receptor (TCR) to a specific peptide-MHC complex on the tumor cell surface. This binding event triggers the formation of an immunological synapse, leading to the release of cytotoxic molecules like perforin and granzymes, and the secretion of pro-inflammatory cytokines such as IFN-gamma and TNF-alpha, ultimately inducing apoptosis in the target cell (Hivroz & Chemin, Frontiers in Immunology, 2018).