DNAJB1-PRKACA fusion-derived peptide-HLA complex (DNAJB1-PRKACA neoantigen-HLA)

The DNAJB1-PRKACA fusion-derived peptide-HLA complex is a highly specific tumor neoantigen found in nearly all cases of fibrolamellar hepatocellular carcinoma (FLC). This complex arises from a recurrent 400-kb deletion on chromosome 19, which creates a chimeric protein combining the N-terminus of the heat shock protein DNAJB1 with the C-terminus of the catalytic subunit of protein kinase A (PRKACA) (Honeyman et al., 2014, Science). The unique amino acid sequence at the fusion junction is processed into peptides and presented by HLA class I and II molecules, making it an ideal target for immunotherapy because it is not expressed in normal tissues (Bauer et al., 2022, Nature Communications). Current therapeutic approaches include the development of T-cell receptor (TCR) engineered T-cells and peptide-based vaccines designed to elicit a cytotoxic T-lymphocyte response against FLC cells (Scurti et al., 2020, Frontiers in Immunology). Clinical trials are investigating these modalities, often requiring patients to possess specific HLA alleles, such as HLA-A*02:01, for effective peptide presentation and recognition (NCT04248569). While the target offers high specificity, potential challenges include tumor immune evasion via the downregulation of HLA molecules or other components of the antigen-processing machinery.

Other names

DNAJB1-PRKACA neoantigenFLC fusion peptide-HLA complexDNAJB1-PRKACA junctional peptide-MHC complex

The target functions as a neoepitope presented on the surface of tumor cells; therapeutic agents such as TCR-T cells or vaccines work by facilitating the recognition of this complex by the immune system, leading to the selective destruction of cells expressing the DNAJB1-PRKACA fusion protein (Bauer et al., 2022, Nature Communications).