Tumor neoantigen peptide-Human Leukocyte Antigen complex (pHLA)

The Tumor neoantigen peptide-Human Leukocyte Antigen (HLA) complex is a molecular assembly presented on the surface of cancer cells, consisting of a somatic mutation-derived peptide bound to an HLA molecule [Frontiers in Immunology, 2020]. These complexes serve as highly specific markers of malignancy because the neoantigens they present are absent from the normal human proteome, thereby bypassing central thymic tolerance [Nature, 2017]. Recognition of these complexes by the T-cell receptor (TCR) is the fundamental step in the adaptive immune system's ability to identify and destroy tumor cells. Therapeutic interventions, such as personalized mRNA vaccines and TCR-engineered T-cell (TCR-T) therapies, are designed to prime or provide the immune system with the necessary tools to target these specific pHLA structures [Science, 2019]. While highly promising for precision oncology, the efficacy of targeting these complexes can be limited by the heterogeneous expression of neoantigens within a tumor and the active downregulation of HLA molecules by cancer cells to escape immune detection [Cell, 2018]. Furthermore, the high degree of polymorphism in HLA genes requires patient-specific matching for many of these therapies, presenting a significant logistical challenge in drug development [Nature Reviews Drug Discovery, 2021].

Other names

Neoepitope-HLA complexTumor-specific antigen-MHC complexpMHC complexMutant peptide-HLA complexNeoantigen-MHC class I complex

The primary mechanism involves the high-affinity binding of a T-cell receptor (TCR) or a TCR-like antibody to the specific neoantigen peptide-HLA complex, which triggers a signaling cascade in the T-cell leading to the release of perforins and granzymes, ultimately causing the apoptotic death of the target tumor cell [Nature Reviews Cancer, 2021].