Mutant Cyclin-dependent kinase inhibitor 2A-derived neoantigen peptides presented by Human Leukocyte Antigen (Mutant CDKN2A-HLA complex)

Mutant CDKN2A-derived neoantigen peptides presented by HLA are tumor-specific antigens that arise from somatic mutations in the CDKN2A gene, which encodes the p16INK4a and p14ARF tumor suppressor proteins (UniProt P42771) [1]. These mutations, particularly frameshifts or non-synonymous substitutions, result in novel peptide sequences that are entirely absent from the normal human proteome, making them highly specific targets for the immune system with minimal risk of central tolerance [2]. Once these mutant proteins are processed by the proteasome, the resulting neoantigenic peptides are loaded onto Human Leukocyte Antigen (HLA) molecules and presented on the cell surface [3]. T-cell receptors (TCRs) on CD8+ or CD4+ T cells can specifically recognize these peptide-HLA complexes, initiating a targeted anti-tumor immune response [4]. Therapeutic strategies currently in development include personalized neoantigen vaccines (mRNA or peptide-based) and adoptive cell therapies, such as TCR-engineered T cells designed to bind specifically to these unique complexes [5]. Given that CDKN2A is one of the most frequently mutated genes in human cancers, including melanoma and pancreatic ductal adenocarcinoma, these neoantigens represent a significant opportunity for precision oncology and personalized immunotherapy [6].

Other names

CDKN2A neoantigensp16INK4a mutant peptidesp14ARF mutant peptidesCDKN2A-derived tumor-specific antigensMutant p16-HLA complexCDKN2A-derived TSA

Recognition of the mutant peptide-HLA complex by the T-cell receptor (TCR) of CD8+ cytotoxic T cells or CD4+ helper T cells, which triggers T-cell activation, cytokine release (e.g., IFN-gamma), and direct lysis of the tumor cell presenting the neoantigen.