Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion
Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion
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DOI：
10.1093/jnci/djy209
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发表时间：
2019-09-01
影响因子：
10.3
通讯作者：
Mackall, Crystal L.
中科院分区：
文献类型：
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作者：
Heitzeneder, Sabine;Sotillo, Elena;Mackall, Crystal L.
背景：尤文肉瘤 (EWS) 是所有癌症中体细胞突变率最低的一种，导致可药物突变和新抗原的稀缺。针对差异表达的细胞表面抗原的免疫治疗可以为此类肿瘤提供治疗益处。妊娠相关血浆蛋白 A (PAPP-A) 是一种由胎盘产生的细胞膜相关蛋白酶，通过诱导胰岛素样生长因子 (IGF) 信号传导促进胎儿生长。方法：通过比较 EWS (n = 120) 与正常组织 (n = 42) 中细胞表面蛋白的 RNA 表达，我们全面表征了 EWS 的表面组，以识别高度差异表达的分子。使用 CRISPR/Cas-9 和抗 PAPP-A 抗体，我们在体外和体内 NSG 异种移植模型中研究了 PAPP-A 在 EWS 中的生物学作用，并对 PAPPA 敲除克隆 (n = 5) 和对照 (n = 3) 进行了 RNA 测序。所有统计检验均为双向。结果：EWS表面组分析鉴定出11个高度差异过表达基因，其中PAPPA差异表达位居第二。在 EWS 细胞系中，PAPPA 基因敲除和抗 PAPP-A 抗体处理揭示了通过调节局部 IGF-1 生物利用度发挥重要的生存作用。 MAb 介导的 PAPPA 抑制减少了原位异种移植物中的 EWS 生长（第 49 天 IgG2a 对照 (CTRL) [n = 14] 时腿部面积 mm(2) [n = 14]，平均值 = 397.0，SD = 86.1 与抗 PAPP-A [n = 14] 相比，平均值 = 311.7，SD = 155.0；P = 0.03；中位 OS 抗 PAPP-A = 52.5 天，95% CI = 46.0 至 63.0 天 vs IgG2a = 45.0 天，95% CI = 42.0 至 52.0 天；P = 0.02）并提高抗 IGF-1R 治疗的疗效（第 49 天抗 PAPP-A + 抗 IGF-1R [n = 15]，腿部面积 mm(2)，平均值 = 217.9，SD = 148.5 对比 IgG2a-CTRL；
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 insulin like growth factor (IGF) signaling.Methods: By comparing RNA expression of cell surface proteins in EWS (n = 120) versus normal tissues (n = 42), 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 (n = 5) and controls (n = 3). 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 mm(2) at day 49 IgG2a control (CTRL) [n = 14], mean = 397.0, SD = 86.1 vs anti-PAPP-A [n = 14], mean = 311.7, SD = 155.0; P = .03; median OS anti-PAPP-A = 52.5 days, 95% CI = 46.0 to 63.0 days vs IgG2a = 45.0 days, 95% CI = 42.0 to 52.0 days; P = .02) and improved the efficacy of anti-IGF-1R treatment (leg area mm(2) at day 49 anti-PAPP-A + anti-IGF-1R [n = 15], mean = 217.9, SD = 148.5 vs IgG2a-CTRL; P