T-cell receptor–Major Histocompatibility Complex–neoantigen peptide complex (TCR-pMHC (Neoantigen))

The T-cell receptor (TCR) recognition of Major Histocompatibility Complex (MHC)–neoantigen peptide complexes is a pivotal mechanism in precision oncology and immunotherapy [1]. Neoantigens are unique, non-self peptides resulting from tumor-specific somatic mutations, which are processed and presented by MHC molecules on the surface of malignant cells [1, 2]. Because these antigens are absent from healthy tissues, they provide a highly specific target for the immune system, theoretically minimizing the risk of autoimmune toxicity [2]. Therapeutic approaches targeting this interaction include personalized neoantigen vaccines, such as mRNA-4157 and BNT122, which stimulate the patient's own T cells, and TCR-engineered T-cell (TCR-T) therapies, where T cells are modified to express receptors specific to a particular neoantigen-MHC pair [3, 4]. This target class is highly dependent on the patient's specific HLA (Human Leukocyte Antigen) type and the unique mutational profile of their tumor [2]. Despite its potential, challenges such as tumor heterogeneity, the complexity of neoantigen prediction, and the potential for immune escape through MHC loss remain significant hurdles in clinical development [3, 4]. Sources: [1] Schumacher & Schreiber (2015) Science; [2] Blass & Ott (2021) Nat Rev Clin Oncol; [3] Zhao et al. (2021) Cell Biosci; [4] Sahin & Türeci (2018) Science.

Other names

Neoantigen-MHC complexTCR-pMHC complexTumor-specific antigen-MHC complexMutant peptide-MHC complexTCR-neoantigen interaction

Therapeutic intervention via engineered T-cell receptors (TCR-T) or vaccines that induce endogenous T-cells to recognize and eliminate cells presenting mutant neoantigen peptides on MHC molecules.