Deng Chuangzhong, Li Zaishang, Guo Shengjie, Chen Peng, Chen Xiaofeng, Zhou Qianghua, Chen Jieping, Yu Xingsu, Wu Xiaoliang, Ma Wenjuan, Xie Qiankun, Ye Yunlin, Li Yonghong, Qin Zike, Liu Zhuowei, Liu Ranyi, Zhang Zhenfeng, Yao Kai, Han Hui, Zhou Fangjian
Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; State Key Laboratory of Oncology in Southern China, Guangzhou, P.R. China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, P.R. China.
Department of Urology, Affiliated Oncological Hospital of Xinjiang Medical University , Xinjiang, P.R. China.
Oncoimmunology. 2016 Dec 22;6(2):e1269047. doi: 10.1080/2162402X.2016.1269047. eCollection 2017.
Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumor-infiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8 TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNγ) and CD8 gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNγ stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma.
尽管阴茎鳞状细胞癌（PeSCC）在全球发病率较低，但由于晚期患者，尤其是发展中国家患者的治疗选择有限，其仍具有较高的发病率和死亡率。程序性死亡受体1（PD-1）/PD-1配体（PD-L1）轴已被证明在肿瘤免疫逃逸中起重要作用，针对该途径的免疫疗法在某些癌症类型中已取得巨大成功。在此，我们通过多中心队列分析了PD-L1在PeSCC肿瘤细胞和肿瘤浸润淋巴细胞（TILs）中的表达模式。我们发现大多数PeSCC（53.4%）为PD-L1阳性，且肿瘤细胞中高PD-L1表达与预后不良相关。值得注意的是，肿瘤细胞中的PD-L1表达与TILs和CD8 TILs的程度显著相关。定量逆转录聚合酶链反应（qRT-PCR）显示PD-L1与干扰素-γ（IFNγ）和CD8基因表达呈正相关。此外，我们确定了新建立的原发性PeSCC细胞系中PD-L1的组成性和诱导性表面表达。有趣的是，两个PeSCC细胞系具有较高的固有PD-L1表达。另一个细胞系显示低PD-L1表达，但PD-L1表达可被IFNγ刺激诱导。总体而言，我们的数据表明阴茎肿瘤细胞中高PD-L1表达提示预后不良。PeSCC中PD-L1的上调包括外在和内在机制。这些发现表明PD-1/PD-L1轴可能是阴茎鳞状细胞癌患者的潜在治疗靶点。
