Tumor antigen–Major Histocompatibility Complex–T-cell receptor complex (pMHC-TCR complex)

The Tumor antigen–Major Histocompatibility Complex–T-cell receptor (Tumor antigen–MHC–TCR) complex is the fundamental structural unit responsible for the specific recognition of cancer cells by T lymphocytes. This tripartite complex forms when a T-cell receptor (TCR) binds to a specific peptide fragment, derived from a tumor-associated or tumor-specific antigen, which is displayed by a Major Histocompatibility Complex (MHC) molecule on the surface of a tumor cell (Rossjohn et al., 2015, Nature Reviews Immunology). The formation of this complex triggers a cascade of intracellular signaling events within the T cell, leading to its activation, proliferation, and the subsequent execution of effector functions such as the release of cytotoxic granules to induce tumor cell lysis (June et al., 2018, Nature). Because this interaction is highly specific to the peptide-MHC combination, it serves as a precise target for advanced immunotherapies, including TCR-engineered T-cell (TCR-T) therapies and soluble TCR-bispecific molecules like Tebentafusp (Nathan et al., 2022, NEJM). However, the therapeutic application is complicated by the diversity of HLA alleles across the human population and the potential for off-target toxicity if the TCR recognizes similar peptides presented on healthy tissues (Linette et al., 2013, Blood).

Other names

Peptide-MHC-TCR complexpMHC-TCR complexTumor-specific TCR-pMHC complexImmunological synapse complex

Redirection and activation of T-cells to specifically lyse tumor cells presenting the cognate antigen-MHC complex.