Human leukocyte antigen class I-tumor neoantigen peptide complex (HLA-I-neoantigen complex)

The patient-specific HLA class I-tumor neoantigen peptide complex is a molecular assembly consisting of a polymorphic human leukocyte antigen (HLA) class I molecule and a peptide derived from a tumor-specific somatic mutation. These complexes are expressed on the surface of malignant cells and serve as the primary signal for recognition by the host's immune system, specifically CD8+ cytotoxic T cells (PubMed: 33407441). Because neoantigens arise from mutations unique to the tumor, such as non-synonymous single nucleotide variants or frameshifts, they are generally absent from healthy tissues, providing a high degree of therapeutic specificity (Nature: 10.1038/s41568-018-0066-5). Therapeutic strategies targeting these complexes include personalized cancer vaccines, which prime the immune system to recognize these specific pMHC (peptide-MHC) combinations, and adoptive T-cell therapies using engineered T-cell receptors (TCRs) (Science: 10.1126/science.aau5905). The primary challenge in targeting these complexes lies in the high degree of HLA polymorphism and the unique mutational landscape of each patient, requiring a bespoke approach to drug development. Additionally, tumors may evade detection by downregulating HLA expression or through other components of the tumor microenvironment (Cell: 10.1016/j.cell.2017.11.017). Clinical trials for personalized vaccines like mRNA-4157 have demonstrated the potential of this target to improve outcomes in melanoma and other solid tumors.

Other names

MHC class I-neoantigen complexNeoantigen-HLA complexTumor-specific antigen-HLA complexpMHC complexNeoepitope-HLA complex

Presentation of tumor-specific mutant peptides to the T-cell receptor (TCR) of CD8+ cytotoxic T lymphocytes, leading to targeted destruction of cancer cells.