Department of Pathology, Faculty of Medicine, Ankara University, Ankara, Turkey.
Department of Urology, Faculty of Medicine, Ankara University, Ankara, Turkey.
Turk J Med Sci. 2022 Dec;52(6):1802-1813. doi: 10.55730/1300-0144.5526. Epub 2022 Dec 21.
Intravesical BCG treatment fails inexplicably in 30%-45% of patients for high-grade nonmuscle-invasive bladder cancer (NMIBC). We aimed to investigate the role of PD-1/PD-L1 interaction on BCG failure of high-grade NMIBC and to identify biomarkers for predicting BCG responsive cases.
Thirty BCG responsive and 29 nonresponsive NMIBCs were included in the study. Expressions of PDL1(SP-263), MSH2, MSH6, PMS2, and MLH1 were evaluated on pre- and post-BCG transurethral resection (TUR-B) specimens by immunohistochemistry. PD-L1(SP-263) expression was categorised as negative/low, high. DNA mismatch repair protein (MMR) expressions were classified as "reduced" if ≤30% of nuclei stained, "preserved" if >30% of nuclei stained. Microsatellite instability (MSI) testing was performed by PCR using five mononucleotide markers.
Reduced DNA MMR protein expression was found to be significantly higher in the pretreatment biopsies of BCG-responsive group than the BCG nonresponsive tumour group (p = 0.022). PD-L1 expression did not show any significant difference between the pre- and posttreatment TUR-B specimens of the BCG nonresponsive tumour group or between the pretreatment TUR-B specimens of BCG nonresponsive and the BCG responsive groups (p = 0.508, p = 0.708, respectively).
Immune escape of tumour cells by PD-1/PD-L1 interaction does not seem to have any role in BCG failure of NMIBCs. Reduced MMR expression may help to determine cases that will respond well to BCG therapy. A better antitumour activity of BCG in NMIBCs with reduced MMR expression may be related to the ongoing accumulation of cancer neoantigens in correlation with increased tumour mutation load as a result of DNA repair defects.
对于高级别非肌肉浸润性膀胱癌（NMIBC），30% 至 45%的患者接受膀胱内卡介苗（BCG）治疗后会出现无法解释的失败。我们旨在研究 PD-1/PD-L1 相互作用在高级别 NMIBC 中 BCG 失败的作用，并确定预测 BCG 反应性病例的生物标志物。
本研究纳入了 30 例 BCG 反应性和 29 例非反应性 NMIBC 患者。采用免疫组织化学法检测术前和 BCG 经尿道膀胱肿瘤切除术（TUR-B）标本中 PDL1（SP-263）、MSH2、MSH6、PMS2 和 MLH1 的表达。PD-L1（SP-263）表达分为阴性/低表达、高表达。如果细胞核染色≤30%，则 DNA 错配修复蛋白（MMR）表达分类为“减少”，如果细胞核染色>30%，则分类为“保留”。采用聚合酶链反应（PCR）用五个单核苷酸标记物进行微卫星不稳定性（MSI）检测。
发现 BCG 反应性组的预处理活检中，DNA MMR 蛋白表达减少的比例明显高于 BCG 无反应性肿瘤组（p = 0.022）。BCG 无反应性肿瘤组的预处理和治疗后 TUR-B 标本之间以及 BCG 无反应性和 BCG 反应性组的预处理 TUR-B 标本之间的 PD-L1 表达均无显著差异（p = 0.508，p = 0.708）。
肿瘤细胞通过 PD-1/PD-L1 相互作用产生的免疫逃逸似乎在 NMIBC 中 BCG 失败中不起作用。MMR 表达减少可能有助于确定对 BCG 治疗反应良好的病例。在 MMR 表达减少的 NMIBC 中，BCG 具有更好的抗肿瘤活性可能与 DNA 修复缺陷导致的肿瘤突变负荷增加相关的癌症新抗原的持续积累有关。
