Tumor-associated fusion protein neoantigen-MHC complex (FPA-MHC)

Tumor-associated fusion protein antigens presented as peptides on MHC molecules represent a unique class of neoantigens resulting from chromosomal rearrangements, such as translocations, inversions, or insertions. These genetic events create chimeric genes that encode novel protein sequences at the fusion junction that are not present in the normal human proteome (Yang et al., 2019). These proteins are processed by the cellular machinery into short peptides, which are then loaded onto Major Histocompatibility Complex (MHC) molecules and displayed on the cell surface for T-cell surveillance (Gao et al., 2018). Because these junctional peptides are entirely tumor-specific, they are highly attractive targets for immunotherapy, offering a high degree of selectivity and a reduced risk of central tolerance-mediated immune escape (Smith et al., 2019). Current therapeutic strategies focusing on these targets include T-cell receptor (TCR) engineered T-cell therapies, personalized peptide or RNA vaccines, and TCR-mimetic antibodies. However, the clinical utility of these antigens is often restricted by the specific HLA haplotype of the patient and the potential for tumor cells to evade the immune system by downregulating MHC expression or other components of the antigen presentation pathway.

Other names

Fusion-derived neoantigensTranslocation-derived MHC-peptide complexesChimeric protein antigensJunctional neoepitopesFusion-derived peptide-HLA complexes

Recognition of the specific fusion-derived peptide sequence presented in the context of a specific HLA molecule by T-cell receptors (TCRs) or TCR-mimetic agents, leading to cytotoxic T-lymphocyte (CTL) activation and targeted lysis of the tumor cell.