[No authors listed]
BACKGROUND:Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling. METHODS:By comparing RNA expression of cell surface proteins in EWS (nâ=â120) versus normal tissues (nâ=â42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (nâ=â5) and controls (nâ=â3). All statistical tests were two-sided. RESULTS:EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [nâ=â14], meanâ=â397.0, SDâ=â86.1 vs anti-PAPP-A [nâ=â14], meanâ=â311.7, SDâ=â155.0; P =â.03; median OS anti-PAPP-Aâ=â52.5âdays, 95% CIâ=â46.0 to 63.0âdays vs IgG2aâ=â45.0âdays, 95% CIâ=â42.0 to 52.0âdays; Pâ=â.02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [nâ=â15], meanâ=â217.9, SDâ=â148.5 vs IgG2a-CTRL; Pâ<â.001; median OS anti-PAPP-A + anti-IGF1Râ=â63.0âdays, 95% CIâ=â52.0 to 67.0âdays vs IgG2a-CTRL; Pâ<â.001). Unexpectedly, PAPPA knockout in EWS cell lines induced interferon (IFN)-response genes, including proteins associated with antigen processing/presentation. Consistently, gene expression profiles in PAPPA-low EWS tumors were enriched for immune response pathways. CONCLUSION:This work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.
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