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

The Neoantigen peptide–Major Histocompatibility Complex–T cell receptor (Neoantigen-pMHC-TCR) complex is a multi-protein assembly that forms the structural basis of the immunological synapse between an antigen-presenting cell, such as a dendritic cell, and a T lymphocyte [1, 6]. This complex consists of a neoantigen—a peptide fragment derived from a tumor-specific somatic mutation—bound within the peptide-binding groove of either a Class I or Class II Major Histocompatibility Complex (MHC) molecule [2, 10]. The pMHC is then recognized by a specific T cell receptor (TCR), triggering a signaling cascade that leads to T cell activation, proliferation, and the subsequent targeted destruction of malignant cells [5, 16]. Because neoantigens are unique to the tumor and absent from healthy tissues, this complex represents an ideal therapeutic target for high-precision immunotherapy, including personalized cancer vaccines and engineered TCR-T cell therapies [3, 18]. Drugs targeting this interaction, such as mRNA-4157 and various adoptive cell transfers, aim to enhance the immune system's ability to detect these subtle genetic alterations [4, 14]. However, the efficacy of such treatments can be limited by tumor heterogeneity, MHC downregulation, and the risk of off-target cross-reactivity with self-peptides [9, 15].

Other names

pMHC-TCR ternary complexNeoantigen-MHC-TCR complexAntigen-specific TCR-MHC complexNeoepitope-MHC-TCR complexpMHC-TCR synapse

Activation of cytotoxic (CD8+) or helper (CD4+) T cells through the specific recognition of tumor-specific mutated peptides presented on MHC molecules, triggering a targeted immune response against malignant cells [1, 5, 16].