Neoantigen–Human Leukocyte Antigen peptide complex (Neoantigen-HLA complex)

Neoantigen–Human Leukocyte Antigen (HLA) peptide complexes are highly specific molecular targets formed when somatic mutations in a tumor's genome result in novel, non-self protein sequences. These mutated proteins are processed by the proteasome into short peptides and presented on the cell surface by HLA molecules, where they can be recognized by the T-cell receptor (TCR) of CD8+ or CD4+ T cells. Unlike tumor-associated antigens, which are also found in normal tissues, neoantigens are strictly tumor-specific, making them ideal targets for immunotherapy with minimal risk of central tolerance or systemic autoimmunity (PMID: 28639998). In the clinical setting, these complexes are targeted through personalized cancer vaccines, such as mRNA-4157 and Autogene cevumeran, which are tailored to an individual patient's unique mutational profile. Additionally, advanced cellular therapies like TCR-T use engineered T cells to specifically home in on these neoepitopes. The therapeutic success of targeting these complexes depends heavily on the stability of the peptide-HLA binding and the presence of a robust T-cell repertoire capable of recognizing the neoantigen as foreign (PMID: 30635039, PMID: 32433940).

Other names

Neoepitope-HLA complexTumor-specific antigen-MHC complexpHLA complexMutation-derived peptide-HLA complexTSA-HLA complex

Neoantigen-HLA complexes serve as the primary recognition signal for the cellular immune system. Therapeutic interventions, such as personalized vaccines, deliver neoantigen sequences to induce the expansion of endogenous T cells that recognize these specific complexes. Other modalities, such as TCR-engineered T cells (TCR-T) or TCR-based bispecifics, utilize synthetic receptors designed to bind the specific peptide-HLA interface with high affinity, triggering direct T-cell mediated lysis of the tumor cell (PMID: 31019023, PMID: 33571551).