Neoantigen–Major Histocompatibility Complex (Neoantigen-MHC)

Neoantigen–Major Histocompatibility Complex (Neoantigen-MHC) complexes are specialized molecular structures on the surface of tumor cells that present mutated protein fragments to the immune system [1, 2]. These complexes are formed when somatic mutations in a cancer cell's DNA result in altered proteins, which are then processed into short peptides (neoantigens) and loaded onto MHC molecules (Human Leukocyte Antigen or HLA in humans) [1, 11]. Because these neoantigens are unique to the tumor and absent in healthy tissues, they serve as highly specific "non-self" signals that can be recognized by T-cell receptors (TCRs) [10, 16]. This recognition is the fundamental step in triggering a targeted cytotoxic T-cell response against the cancer [7, 14]. Therapeutically, Neoantigen-MHC complexes are the focus of several advanced immunotherapy strategies, including personalized cancer vaccines (e.g., mRNA-4157), TCR-engineered T-cell therapies (TCR-T), and TCR-mimic antibodies [1, 11, 16]. These treatments aim to enhance the immune system's ability to identify and destroy cells presenting these specific markers [11, 12]. However, the clinical utility of targeting these complexes is challenged by the high degree of patient-specific variation in mutations and HLA types, as well as tumor-mediated immune escape mechanisms like HLA downregulation [1, 12]. Despite these hurdles, they remain one of the most promising avenues for precision oncology due to their potential for high efficacy and minimal off-target effects [10, 15].

Other names

Neoantigen-HLA complexTumor-specific antigen-MHC complexpHLA complexNeoepitope-MHC complexMutant peptide-MHC complexNeoantigen–HLA peptide–MHC complex

T-cell receptor (TCR) binding, antibody-mediated recognition of peptide-MHC complexes, and recruitment of cytotoxic T lymphocytes (CTLs) to induce tumor cell apoptosis [1, 7, 11].