Ewing sarcoma breakpoint region 1-Friend leukemia integration 1 transcription factor fusion protein-derived neoantigens (EWS-FLI1 neoantigens)

EWS-FLI1 fusion protein-derived neoantigens are unique peptide sequences created at the junction of the EWSR1 and FLI1 genes following a chromosomal translocation, most commonly t(11;22)(q24;q12) (Riggi et al., 2014). This translocation is the hallmark of Ewing sarcoma, occurring in approximately 85% of cases and resulting in an oncogenic transcription factor that drives tumor growth (UniProt P15172). Because the junctional sequence is entirely absent from the normal human proteome, these neoantigens represent highly specific targets for immunotherapy, theoretically minimizing the risk of off-target toxicity in healthy tissues (Evans et al., 2021). Current therapeutic development focuses on utilizing these neoantigens in cancer vaccines or as targets for T-cell receptor (TCR) engineered T-cell therapies, such as those targeting the HLA-A*02:01 restricted junctional peptide (ClinicalTrials.gov NCT03635632). Despite their high specificity, the clinical application is challenged by the low mutational burden of Ewing sarcoma and the frequent downregulation of HLA molecules, which are necessary for antigen presentation to the immune system (Meyer-Wentrup et al., 2005). Successful targeting requires overcoming the immunosuppressive tumor microenvironment characteristic of pediatric sarcomas.

Other names

EWSR1-FLI1 fusion neoantigensEwing sarcoma fusion-derived peptidesEWS-FLI1 junctional peptidesEWS-FLI1 fusion-derived neoepitopes

Targeting of tumor cells through the recognition of fusion-specific junctional peptides presented by Major Histocompatibility Complex (MHC) molecules by engineered T-cell receptors (TCRs) or vaccine-induced immune responses (Evans et al., 2021).