As a prognostic biomarker of clear cell renal cell carcinoma RUFY4 predicts immunotherapy responsiveness in a PDL1-related manner.
As a prognostic biomarker of clear cell renal cell carcinoma RUFY4 predicts immunotherapy responsiveness in a PDL1-related manner.
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DOI：
10.1186/s12935-022-02480-7
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发表时间：
2022-02-08
影响因子：
5.8
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Miao D;Shi J;Xiong Z;Xiao W;Meng X;Lv Q;Xie K;Yang H;Zhang X
肾透明细胞癌(CcRCC)是泌尿系统最致命的恶性肿瘤之一，现有的免疫治疗方法并未取得满意的效果。因此，本研究旨在建立一种新的基因标记来预测肾细胞癌患者的免疫渗透和临床预后(总存活率和免疫治疗反应性)。基于RNA测序数据和癌症基因组图谱(TCGA)数据库中的临床信息，我们使用在线工具CIBERSORTx计算了611个样本中免疫细胞的比例。多因素生存分析确定关键生存相关免疫细胞和免疫渗透相关基因(IIRGs)。接下来，应用临床标本和常见的肾癌细胞系来证实IIRGs在蛋白质和RNA水平的表达。最后，针对RUFY4进行了功能浓缩分析和siRNA技术，以验证其对免疫治疗应答的预测功能。滤泡辅助T细胞(TFHs)和调节性T细胞(Tregs)在肿瘤微环境(TME)中高度渗透，其相对比例是影响患者预后的独立因素。在TFHs和Tregs的IIRGs中，RUFY4在肿瘤微环境中高度激活，其共表达网络在肿瘤中的PDL1/PD1检查点通路中丰富。此外，RUFY4基因敲除导致肾癌细胞株PDL1表达下降，细胞增殖能力下降。TFHs和Tregs被认为是预后的生物标志物，RUFY4是PDL1相关的ccRCC患者的免疫治疗预测因子。网上版载有补充材料，可在10.1186/s12935-022-02480-7查阅。
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. The online version contains supplementary material available at 10.1186/s12935-022-02480-7.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
15.9
作者：
Gu-Trantien, Chunyan;Loi, Sherene;Willard-Gallo, Karen
通讯作者：
Willard-Gallo, Karen
影响因子：
3.9
作者：
Men, Wanfu;Li, Wenya;Gong, Shulei
通讯作者：
Gong, Shulei
影响因子：
8.8
作者：
Garcia-Diaz A;Shin DS;Moreno BH;Saco J;Escuin-Ordinas H;Rodriguez GA;Zaretsky JM;Sun L;Hugo W;Wang X;Parisi G;Saus CP;Torrejon DY;Graeber TG;Comin-Anduix B;Hu-Lieskovan S;Damoiseaux R;Lo RS;Ribas A
通讯作者：
Ribas A
影响因子：
82.9
作者：
Ganesh K;Massagué J
通讯作者：
Massagué J