Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor.
Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor.
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DOI：
10.1158/1535-7163.mct-20-0410
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发表时间：
2020-12
影响因子：
5.7
通讯作者：
Saleem, Mohammad
中科院分区：
文献类型：
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作者：
Ganaie, Arsheed A.;Mansini, Adrian P.;Hussain, Tabish;Rao, Arpit;Siddique, Hifzur R.;Shabaneh, Ashraf;Ferrari, Marina G.;Murugan, Paari;Klingelhofer, Jorg;Wang, Jinhua;Ambartsumian, Noona;Warlick, Christopher A.;Konety, Badrinath R.;Saleem, Mohammad
S100 A4癌蛋白在前列腺癌（CaP）进展过程中起关键作用，并诱导宿主组织中的免疫抑制。我们假设S100 A4调节的免疫抑制前列腺肿瘤的致癌活性促进了肿瘤细胞的生长，这些肿瘤细胞可能变得具有侵袭性。在目前的研究中，我们调查了活检-S100 A4基因改变是否独立预测患者的疾病结局，以及循环-S100 A4是否是治疗免疫抑制性CaP的药物靶点。在DECIPHER基因组检测的帮助下，我们在228例根治性前列腺切除术治疗的患者中显示活检S100 A4过表达可预测（i）ADT反应差和（ii）死亡风险高。此外，对>1000名CaP患者的肿瘤基因组数据的分析（PRAD/SU 2C/FHCRC研究）验证了S100 A4改变与较差存活和转移的关联。我们发现血清S100 A4水平的增加与患者的CaP进展相关。转移的先决条件是肿瘤细胞通过血管系统逃逸。我们发现，细胞外-S100 A4蛋白作为生长因子诱导CaP细胞的血管迁移和骨矿化，从而形成治疗CaP的理想靶点。利用表面等离子体共振和ITC技术，我们证明了mab 6 B12抗体与S100 A4蛋白相互作用并中和S100 A4蛋白。当测试治疗功效时，mab 6 B12抗体疗法减少（i）骨源性MSC的成骨矿化，（ii）CaP细胞中的S100 A4-靶标（NFκB/MMP 9/VEGF），和（iii）免疫充足小鼠模型中的TRAMPC 2-细胞致瘤性。免疫谱分析显示，mAb 6 B12治疗（i）改变了Th 1/Th 2平衡（增加了-Stat 4 +/T-bet+，减少了-GATA 2 +/CD 68 +/CD 45 +/CD 206+细胞），（ii）调节了CD 4 +ve T细胞中的马林水平，和（iii）降低了白细胞介素-5/6/12/13、sTNFR 1和血清RANTES的水平。我们认为，S100 A4抗体疗法在治疗免疫抑制型CaP患者中具有临床适用性。
S100A4 oncoprotein plays a critical role during prostate cancer (CaP) 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 if biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive-CaP. 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 >1000 CaP patients (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 CaP 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 CaP cells and bone-mineralization thus forms an ideal target for therapies for treating CaP. By employing Surface-Plasmon-resonance and ITC, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 antibody-therapy reduced (i) osteoblastic mineralization of bone-derived MSC`s, (ii) S100A4-targets (NFκB/MMP9/VEGF) in CaP-cells, and (iii) TRAMPC2-cell tumorigenicity in an immunosufficient mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased-Stat4+/T-bet+, & decreased-GATA2+/CD68+/CD45+/CD206+ cells), (ii) modulated cytokine-levels in CD4+ve T-cells, and (iii) decreased levels of Interleukin-5/6/12/13, sTNFR1 and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive-CaP in patients.