S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.

中文翻译：

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抗 S100A4 抗体疗法可有效治疗侵袭性前列腺癌和逆转免疫抑制：血清和活检 S100A4 作为临床预测指标

S100A4 癌蛋白在前列腺癌进展过程中起关键作用，并在宿主组织中诱导免疫抑制。我们假设免疫抑制的前列腺肿瘤中 S100A4 调节的致癌活性促进了可能变得具有侵袭性的肿瘤细胞的生长。在目前的研究中，我们调查了活检 S100A4 基因改变是否独立预测患者疾病的结果，而循环 S100A4 是治疗免疫抑制性前列腺癌的药物靶点。在 DECIPHER 基因组测试的帮助下，我们显示活检 S100A4 过表达可预测 228 名接受根治性前列腺切除术治疗的患者的 (i) ADT 反应差和 (ii) 高死亡风险。此外，分析1个以上的肿瘤基因组数据，000 名前列腺癌患者（PRAD/SU2C/FHCRC 研究）证实了 S100A4 改变与较差的生存率和转移之间的关联。我们表明血清-S100A4 水平升高与患者的前列腺癌进展有关。转移的先决条件是肿瘤细胞通过血管系统逃逸。我们表明，作为生长因子的细胞外 S100A4 蛋白可诱导前列腺癌细胞的血管迁移和骨脱矿，从而形成治疗前列腺癌的理想靶标。通过采用表面等离子共振和等温滴定量热法，我们显示 mab6B12 抗体与 S100A4 蛋白相互作用并中和 S100A4 蛋白。当测试治疗效果时，mab6B12 疗法减少了（i）骨源性 MSC 的成骨细胞脱矿质，(ii) 前列腺癌细胞中的 S100A4 靶标 (NFκB/MMP9/VEGF) 水平，以及 (iii) TRAMPC2 同基因小鼠模型中的肿瘤生长。免疫谱分析显示 mAb6B12 治疗 (i) 改变了 Th1/Th2 平衡（增加 Stat4+/T-bet+ 并减少 GATA2+/CD68+/CD45+/CD206+ 细胞）；(ii) CD4+ T 细胞中调节的细胞因子水平；(iii) IL5/6/12/13、sTNFR1 和血清-RANTES 水平降低。我们建议 S100A4 抗体疗法在治疗免疫抑制性前列腺癌患者中具有临床适用性。(iii) IL5/6/12/13、sTNFR1 和血清-RANTES 水平降低。我们建议 S100A4 抗体疗法在治疗免疫抑制性前列腺癌患者中具有临床适用性。(iii) IL5/6/12/13、sTNFR1 和血清-RANTES 水平降低。我们建议 S100A4 抗体疗法在治疗免疫抑制性前列腺癌患者中具有临床适用性。