Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure: A Pilot Study.
Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure: A Pilot Study.
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DOI：
10.3390/jcm10040764
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发表时间：
2021-02-14
影响因子：
3.9
通讯作者：
Thurnher M
中科院分区：
文献类型：
--
作者：
Pichler R;Lindner AK;Schäfer G;Tulchiner G;Staudacher N;Mayr M;Comperat E;Orme JJ;Schachtner G;Thurnher M
虽然卡介苗（BCG）仍然是高风险非肌肉浸润性膀胱癌辅助治疗的主要手段，但高达40%的患者发生BCG失败，根治性环磷酰胺（RC）是不可避免的治疗后果。目前的数据表明，PD-L1免疫抑制信号是BCG失败的原因，支持检查点抑制剂与BCG联合使用的治疗原理。为了解决卡介苗失败后获得的19份RC标本中的免疫级联反应，我们应用了一个由选定标志物（PD-L 1、加塔-3、去整合素和金属蛋白酶（ADAM）蛋白酶、IL-10/IL-10 R）组成的小型免疫组织化学（MHC）组。使用改良的快速评分对两个不同区域内的肿瘤细胞（TC）和免疫细胞（IC）中的这些标志物进行IHC半定量：肌层浸润性膀胱癌（MIBC）和原发性/并发原位癌（CIS）。与预期相反，PD-L1始终较低，与肿瘤区域和细胞类型无关。有趣的是，据报道释放膜结合PD-L1的ADAM 17的表达在肿瘤区域和细胞类型中都很高。此外，GATA 3、IL-10和IL-10 R的表达也增加，表明BCG失败时通常存在免疫抑制性肿瘤微环境。在RC中，ADAM 10表达与晚期肿瘤疾病相关。我们的研究结果提高了ADAM蛋白酶可能从膀胱TC表面切割PD-L1的可能性，也可能从IC切割PD-L1。因此，IHC评估PD-L1表达似乎是不够的，在BCG失败的患者中应补充ADAM 10/17。
Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.
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