Ewing sarcoma immunopeptidomics

Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the EWSR1::FLI1 fusion. Recent reports indicate the EWSR1::FLI1 fusion onco-protein drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOX¬HD1). Given its highly restricted protein expression pattern and role in EwS tumorigenesis and metastasis, LOXHD1 may serve as a novel immunotherapeutic target in this malignancy. LOXHD1 immunogenic epitopes restricted to HLA-A*02:01 allowed for the isolation of high avidity TCRs. LOXHD1-specific TCR engineered CD8+ T cells confer cytotoxic activity against a panel of HLA-A*02:01+ EwS tumor cell lines and adoptive transfer leads to tumor eradication in a mouse xenograft model of EwS. This study nominates LOXHD1 as an onco-fusion regulated / non-mutated EwS tumor associated antigen with expression limited to inner hair cells of the cochlea, adult testis, and EwS