Tumor-specific neoantigen–MHC class I complex (Neoantigen-MHC-I complex)

Tumor-specific neoantigen–MHC class I complexes are molecular assemblies formed by the binding of mutation-derived peptides (neoantigens) to Major Histocompatibility Complex (MHC) class I molecules on the surface of tumor cells or antigen-presenting cells [2.2.1, 2.2.2]. These complexes serve as the primary signal for the adaptive immune system to distinguish malignant cells from healthy tissue, as neoantigens arise from somatic mutations unique to the tumor [3.1.1, 3.1.2]. Recognition of these complexes by CD8+ cytotoxic T-cell receptors (TCRs) triggers a targeted immune response, leading to the destruction of the cancer cell [2.2.1, 3.1.3]. Because neoantigens are absent from normal tissues, they are highly specific therapeutic targets with a low risk of systemic autoimmunity [3.1.3, 3.4.2]. Current therapeutic strategies include personalized mRNA or peptide vaccines designed to prime the immune system against these complexes, as well as adoptive T-cell therapies (TCR-T) and TCR-mimic antibodies that directly target the pMHC-I assembly [3.1.2, 3.3.3]. However, challenges such as MHC downregulation by tumors and the high degree of patient-specific HLA polymorphism necessitate personalized approaches and careful selection of immunogenic epitopes [2.2.2, 3.1.2].

Other names

Neoantigen-HLA complexPeptide-MHC class I complexpMHC-I complexTumor-specific peptide-MHC complexNeoepitope-MHC complexTumor-specific neoantigen-HLA-A/B/C complex

Therapeutic agents target these complexes through various modalities: personalized vaccines (mRNA, DNA, or peptide) induce de novo T-cell responses by presenting neoantigens on MHC; TCR-engineered T-cell (TCR-T) therapies and TCR-mimic (TCRm) antibodies directly recognize the complex to mediate tumor cell lysis; and bispecific T-cell engagers (BiTEs) bridge the complex with CD3 on T cells to trigger cytotoxicity [3.1.2, 3.3.3, 3.4.2].