Ewing sarcoma breakpoint region 1-Friend leukemia integration 1 transcription factor fusion protein-derived peptides presented on Major Histocompatibility Complex (EWS-FLI1-MHC complex)

The EWS-FLI1 fusion protein is the pathognomonic driver of Ewing sarcoma, resulting from a reciprocal chromosomal translocation between the EWSR1 and FLI1 genes [PMID: 32814744]. As an intracellular transcription factor, EWS-FLI1 is largely inaccessible to traditional monoclonal antibodies; however, its degradation products are processed and presented on the cell surface by Major Histocompatibility Complex (MHC) molecules [PMID: 25103445]. Peptides spanning the unique fusion junction or specific sequences within the fusion protein function as tumor-specific neoantigens that can be recognized by T-cell receptors (TCRs). Therapeutic strategies targeting these complexes include TCR-engineered T cells (TCR-T) and TCR-mimetic bispecific antibodies designed to bind the specific peptide-MHC complex with high affinity [PMID: 33613474]. This approach allows for highly selective targeting of malignant cells while theoretically sparing healthy tissues that lack the fusion protein. The clinical success of this target depends on the stability of the peptide-MHC interaction and the patient's specific HLA haplotype, most commonly HLA-A*02:01.

Other names

EWS-FLI1 neoantigenEWS-FLI1 junctional peptidesEWS-FLI1 HLA-restricted peptidesEWSR1-FLI1 fusion peptidesEWS-FLI1 pMHC

T-cell receptor-mediated recognition of tumor-specific fusion peptides presented on MHC molecules, leading to targeted cytotoxic T-lymphocyte (CTL) lysis of Ewing sarcoma cells.