Miao Daojia, Shi Jian, Xiong Zhiyong, Xiao Wen, Meng Xiangui, Lv Qingyang, Xie Kairu, Yang Hongmei, Zhang Xiaoping
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cancer Cell Int. 2022 Feb 8;22(1):66. doi: 10.1186/s12935-022-02480-7.
Clear cell renal cell carcinoma (ccRCC) is one of the most lethal malignancies in the urinary system and the existing immunotherapy has not achieved satisfactory outcomes. Therefore, this study aims at establishing a novel gene signature for immune infiltration and clinical outcome (overall survival and immunotherapy responsiveness) in ccRCC patients.
Based on RNA sequencing data and clinical information in The Cancer Genome Atlas (TCGA) database, we calculated proportions of immune cells in 611 samples using an online tool CIBERSORTx. Multivariate survival analysis was conducted to determine crucial survival-associated immune cells and immune-infiltration-related genes (IIRGs). Next, the clinical specimens and common renal cancer cell lines were applied to confirm IIRGs expression at protein and RNA levels. Finally, functional enrichment analyses and siRNA technology targeted to RUFY4 were implemented to verify its function of predicting immunotherapy response.
Follicular helper T cells (TFHs) and Regulatory T cells (Tregs) were highly infiltrated in the tumor microenvironment (TME) and their relative proportions were independent prognostic factors for patients. Among IIRGs of TFHs and TREGs, RUFY4 was found to be highly activated in tumor microenvironment and its co-expression network was enriched in PDL1/PD1 checkpoint pathway in cancer. Additionally, knockdown of RUFY4 led to the decline of PDL1 and proliferation ability in ccRCC cell lines.
TFHs and Tregs were considered as prognostic biomarkers and RUFY4 was an immunotherapeutic predictor of ccRCC patients in a PDL1-Related manner.
透明细胞肾细胞癌（ccRCC）是泌尿系统中最致命的恶性肿瘤之一，现有的免疫疗法尚未取得令人满意的效果。因此，本研究旨在为ccRCC患者建立一种新的免疫浸润和临床结局（总生存期和免疫治疗反应性）基因特征。
基于癌症基因组图谱（TCGA）数据库中的RNA测序数据和临床信息，我们使用在线工具CIBERSORTx计算了611个样本中免疫细胞的比例。进行多变量生存分析以确定关键的生存相关免疫细胞和免疫浸润相关基因（IIRGs）。接下来，应用临床标本和常见肾癌细胞系在蛋白质和RNA水平上确认IIRGs的表达。最后，实施功能富集分析和靶向RUFY4的siRNA技术以验证其预测免疫治疗反应的功能。
滤泡辅助性T细胞（TFHs）和调节性T细胞（Tregs）在肿瘤微环境（TME）中高度浸润，它们的相对比例是患者的独立预后因素。在TFHs和Tregs的IIRGs中，发现RUFY4在肿瘤微环境中高度激活，其共表达网络在癌症的PDL1/PD1检查点通路中富集。此外，敲低RUFY4导致ccRCC细胞系中PDL1水平下降和增殖能力降低。
TFHs和Tregs被认为是预后生物标志物，RUFY4是以与PDL1相关的方式作为ccRCC患者免疫治疗的预测指标。
