Patient-specific tumor neoantigen–Major Histocompatibility Complex and T cell receptor complex (Neoantigen-MHC-TCR)

Patient-specific tumor neoantigen–Major Histocompatibility Complex (MHC) and T cell receptor (TCR) complexes are the fundamental units of recognition in personalized cancer immunotherapy (Schumacher & Schreiber, Science 2015). Neoantigens are novel peptides arising from somatic mutations unique to an individual's tumor, which are not found in the normal genome and thus bypass central thymic tolerance (Blass & Ott, Nature Reviews Clinical Oncology 2021). These peptides are presented on the tumor cell surface by MHC molecules (specifically Human Leukocyte Antigens or HLA in humans) to be recognized by the TCRs of CD8+ or CD4+ T cells. This interaction is highly specific, making it an ideal target for therapeutic interventions such as personalized neoantigen vaccines and TCR-engineered T cell (TCR-T) therapies (Sahin & Türeci, Science 2018). By targeting these unique complexes, treatments aim to elicit a robust, tumor-specific immune response while sparing healthy tissues from off-target effects. However, the clinical success of targeting these complexes depends on accurate neoantigen prediction, the diversity of the patient's TCR repertoire, and the tumor's ability to downregulate MHC expression to evade detection (Gubin et al., Nature 2014).

Other names

Neoantigen-HLA-TCR complexTumor-specific neoepitope-MHC complexPersonalized TCR-T target axisNeoantigen-MHC-TCR interaction

The therapeutic mechanism involves the recognition of tumor-specific neoantigens presented by MHC molecules by either vaccine-induced endogenous T cells or adoptively transferred TCR-engineered T cells, leading to the formation of an immunological synapse and subsequent cytotoxic destruction of the tumor cell (June et al., Science 2018; Blass & Ott, Nature Reviews Clinical Oncology 2021).