Ewing sarcoma breakpoint region 1-Friend leukemia virus integration 1 fusion-derived peptide–Major Histocompatibility Complex (EWS-FLI1-pMHC) (EWS-FLI1-pMHC)

The EWS-FLI1 fusion-derived peptide–Major Histocompatibility Complex (EWS-FLI1-pMHC) is a tumor-specific neoantigen target primarily associated with Ewing sarcoma, a pediatric malignancy (National Cancer Institute, 2023). This complex is formed when the unique junctional peptide sequence created by the t(11;22)(q24;q12) chromosomal translocation is processed and presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, most commonly HLA-A*02:01 (Evans et al., 2017). Because the EWS-FLI1 fusion protein is an intracellular transcription factor, it is traditionally considered "undruggable" by conventional antibodies; however, the presentation of its junctional peptide as a pMHC complex allows for recognition by the cellular immune system (Liu et al., 2020). Therapeutic strategies currently under investigation include T-cell receptor (TCR) engineered T-cells and TCR-like antibodies or bispecifics designed to bind this specific peptide-HLA interface (Meyer-Wentrup et al., 2005). These therapies aim to trigger a potent cytotoxic immune response specifically against Ewing sarcoma cells while sparing normal tissues that lack the fusion protein. Key challenges in targeting this complex include the relatively low density of the pMHC on the cell surface and the potential for tumor escape through MHC class I downregulation (Blaeschke et al., 2016).

Other names

EWS-FLI1 neoantigen-HLA complexEWS-FLI1 junctional peptide-MHCEwing sarcoma fusion peptide-MHCEWS-FLI1-HLA-A*02:01 complex

Recognition of the tumor-specific junctional peptide presented by MHC by engineered T-cell receptors (TCRs) or TCR-like molecules, leading to targeted lysis of Ewing sarcoma cells.