Neoantigen peptide–Human Leukocyte Antigen complex (pHLA) (pHLA)

Neoantigen peptide–Human Leukocyte Antigen (HLA) complexes are cell-surface structures composed of a mutant peptide fragment derived from tumor-specific somatic mutations bound to an HLA molecule. These complexes serve as the primary signal for the adaptive immune system to distinguish malignant cells from healthy tissue, as the mutant peptides (neoantigens) are not present in the normal human proteome (Schumacher & Schreiber, 2015, Science). Recognition of these complexes by T-cell receptors (TCRs) on cytotoxic T lymphocytes triggers a targeted immune response aimed at eliminating the tumor (Blass & Ott, 2021, Nature Reviews Clinical Oncology). Because neoantigens arise from random mutations, they are typically unique to each patient, necessitating personalized therapeutic approaches (Yarchoan et al., 2017, Nature Reviews Cancer). Therapeutic interventions targeting these complexes include personalized mRNA or peptide vaccines designed to expand endogenous neoantigen-specific T cells, as well as adoptive cell therapies using T cells engineered with specific TCRs. Additionally, bispecific molecules and TCR-like antibodies are being developed to directly bind these complexes and recruit immune effector cells. While highly specific, the clinical utility of targeting neoantigen-HLA complexes is challenged by the high degree of inter-patient variability and the potential for tumors to escape immune detection through the downregulation of HLA expression (Hollingsworth & Jansen, 2019, Nature Reviews Genetics).

Other names

Neoepitope-HLA complexMutant peptide-MHC complexpMHCTumor-specific antigen-HLA complexNeoantigen-MHC complex

Recognition by neoantigen-specific T-cell receptors (TCRs) leading to the activation of cytotoxic T lymphocytes and selective destruction of tumor cells presenting the mutant peptide.