Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Eur Urol Oncol. 2021 Feb;4(1):117-120. doi: 10.1016/j.euo.2019.01.017. Epub 2019 Feb 26.
Anti-PD-L1/PD-1 immunotherapy has improved survival for certain patients with metastatic urothelial carcinoma. However, the mechanisms of resistance to these agents have not been fully elucidated. We report the first combined analysis using RNA sequencing, whole-exome sequencing (WES), and flow cytometry of multiple tumor specimens over a 5-yr period for a patient undergoing anti-PD-L1 therapy. Initial sensitivity to anti-PD-L1 immunotherapy was associated with conversion to a basal molecular subtype and a rising tumor mutational burden. We found that as the tumor became more resistant to anti-PD-L1, the proportion of regulatory T cells and CD8 T cells expressing alternative immune checkpoints including CTLA-4, TIM-3, and LAG-3 increased. This suggests that alternative immune checkpoint upregulation may be one form of anti-PD-L1 resistance in urothelial carcinoma. These data support the concept of combined immune checkpoint blockade for urothelial carcinoma, a concept that is being evaluated in prospective clinical trials. PATIENT SUMMARY: In this study we characterized how a patient with metastatic urothelial cancer became resistant to anti-PD-L1 immunotherapy. By tracking changes in protein and gene expression over time, we found that as urothelial carcinoma becomes resistant to PD-L1 blockade, additional immune checkpoints may be upregulated. These data support the concept of combined checkpoint blockade for urothelial carcinoma.
抗 PD-L1/PD-1 免疫疗法改善了某些转移性尿路上皮癌患者的生存。然而，这些药物耐药的机制尚未完全阐明。我们报告了首例对一名接受抗 PD-L1 治疗的患者的多个肿瘤标本进行 RNA 测序、全外显子测序 (WES) 和流式细胞术的联合分析。对抗 PD-L1 免疫治疗的初始敏感性与转化为基底分子亚型和肿瘤突变负担增加有关。我们发现，随着肿瘤对抗 PD-L1 的耐药性增加，表达替代免疫检查点（包括 CTLA-4、TIM-3 和 LAG-3）的调节性 T 细胞和 CD8 T 细胞的比例增加。这表明替代免疫检查点上调可能是尿路上皮癌抗 PD-L1 耐药的一种形式。这些数据支持联合免疫检查点阻断治疗尿路上皮癌的概念，这一概念正在前瞻性临床试验中进行评估。
在这项研究中，我们描述了一名转移性尿路上皮癌患者如何对抗 PD-L1 免疫疗法产生耐药性。通过跟踪随时间推移的蛋白和基因表达变化，我们发现随着尿路上皮癌对 PD-L1 阻断的耐药性增加，可能会上调其他免疫检查点。这些数据支持联合检查点阻断治疗尿路上皮癌的概念。
