Department of Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, 35043, Baldingerstraße Marburg, Germany.
Immunoanalytics Research Group Tissues Control of Immunocytes, Helmholtz Zentrum München, National Research Center for Environmental Health, Munich, Germany.
Target Oncol. 2020 Jun;15(3):377-390. doi: 10.1007/s11523-020-00728-8.
Programmed death ligand (PD-L1)-based immune checkpoint blockade therapy for metastatic renal cell carcinoma (RCC) achieves significant response rates in a subgroup of patients. The relevance of PD-L1 gene regulation for disease outcome is not clear.
To evaluate PD-L1 expression and its dependence on interferon-γ (IFN-γ) in RCC cell lines and tissues in relation to disease outcome.
Regulation of PD-L1-mRNA and PD-L1 protein was studied in cell lines from clear cell RCC (ccRCC) and papillary RCC (pRCC) by quantitative RT-PCR and Western-blot analysis. PD-L1-mRNA correlation and gene-set enrichment analysis (GSEA) of the IFN-γ pathway were conducted with RNA-Seq from ccRCC, pRCC, and skin cutaneous melanoma (SKCM) tissue. In addition, patient overall survival (OS) and disease-free survival (DFS) (cBioPortal for Cancer Genomics) were considered.
In ccRCC-like cell lines, PD-L1 was induced by canonical IFN-γ signaling, whereas in a pRCC-like cell line, PD-L1 was refractory towards IFN-γ signaling. In ccRCC and SKCM tissues, GSEA revealed significant IFN-γ pathway activation in tissue samples with high PD-L1-mRNA levels. This was not observed in pRCC tissue. ccRCC and SKMC patients with low PD-L1-mRNA levels had significantly shorter OS and DFS than those with high PD-L1-mRNA levels. In pRCC patients, no significant difference in OS and DFS with regard to PD-L1-mRNA tissue levels was obvious.
The findings suggest that ccRCC and pRCC differ with respect to PD-L1 regulation by IFN-γ-signaling. High PD-L1-mRNA levels in tumor tissues with a positive IFN-γ signature favorably affect OS and DFS.
程序性死亡配体 (PD-L1) 为基础的免疫检查点阻断疗法在转移性肾细胞癌 (RCC) 的亚组患者中取得了显著的反应率。PD-L1 基因调控对疾病结局的相关性尚不清楚。
评估 PD-L1 表达及其在 RCC 细胞系和组织中对疾病结局的影响与干扰素-γ (IFN-γ) 的相关性。
通过定量 RT-PCR 和 Western-blot 分析研究了来自透明细胞肾细胞癌 (ccRCC) 和乳头状肾细胞癌 (pRCC) 的细胞系中 PD-L1-mRNA 和 PD-L1 蛋白的调节。对 ccRCC、pRCC 和皮肤黑色素瘤 (SKCM) 组织的 RNA-Seq 进行了 PD-L1-mRNA 相关性和 IFN-γ 通路基因集富集分析 (GSEA)。此外，还考虑了患者的总生存期 (OS) 和无病生存期 (DFS) (cBioPortal for Cancer Genomics)。
在 ccRCC 样细胞系中，PD-L1 被经典的 IFN-γ 信号诱导，而在 pRCC 样细胞系中，PD-L1 对 IFN-γ 信号无反应。在 ccRCC 和 SKCM 组织中，GSEA 显示高 PD-L1-mRNA 水平的组织样本中存在明显的 IFN-γ 通路激活。在 pRCC 组织中没有观察到这种情况。PD-L1-mRNA 水平低的 ccRCC 和 SKMC 患者的 OS 和 DFS 明显短于 PD-L1-mRNA 水平高的患者。在 pRCC 患者中，OS 和 DFS 与 PD-L1-mRNA 组织水平之间无明显差异。
这些发现表明，ccRCC 和 pRCC 在 PD-L1 受 IFN-γ 信号调节方面存在差异。肿瘤组织中高 PD-L1-mRNA 水平与阳性 IFN-γ 特征对 OS 和 DFS 有利。
