EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.
EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.
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DOI：
10.1038/s41467-018-05992-x
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发表时间：
2018-08-29
影响因子：
16.6
通讯作者：
Galsky MD
中科院分区：
文献类型：
--
作者：
Wang L;Saci A;Szabo PM;Chasalow SD;Castillo-Martin M;Domingo-Domenech J;Siefker-Radtke A;Sharma P;Sfakianos JP;Gong Y;Dominguez-Andres A;Oh WK;Mulholland D;Azrilevich A;Hu L;Cordon-Cardo C;Salmon H;Bhardwaj N;Zhu J;Galsky MD
浸润有T细胞的癌症与对PD-1/PD-L1阻断的反应的更高可能性相关。与直觉相反的是，在不同肿瘤类型中观察到上皮-间质转化（EMT）相关基因表达与T细胞浸润之间的相关性。在这里，我们使用癌症基因组图谱（TCGA）尿路上皮癌数据集证明，尽管基于基因表达的浸润性T细胞丰度和EMT相关基因表达的测量呈正相关，但这些特征传达了不同的预后信息。我们进一步证明了非造血基质细胞是大量尿路上皮癌转录组中EMT相关基因表达的主要来源。最后，使用PD-1抑制剂nivolumab治疗的转移性尿路上皮癌患者队列，我们证明在T细胞浸润肿瘤患者中，EMT/基质相关基因表达较高与缓解率较低以及无进展生存期和总生存期较短相关。总之，我们的研究结果表明尿路上皮癌中基质介导的免疫抵抗来源，并为共同靶向PD-1和基质成分提供了理论基础。虽然T细胞浸润与尿路上皮癌标本中EMT相关基因表达相关，但作者报告尿路上皮癌中EMT相关特征主要来自基质细胞。T细胞浸润肿瘤中EMT相关基因表达的增加与免疫检查点阻断的减弱反应相关，为治疗性共靶向PD-1和基质成分提供了理论基础。
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial–mesenchymal transition (EMT)-related gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements. Although T-cell infiltration is correlated with EMT-related gene expression in urothelial cancer specimens, here, the authors report EMT-related signatures in urothelial cancer arise mainly from stromal cells. Increased EMT-related gene expression in T-cell infiltrated tumors is associated with an attenuated response to immune checkpoint blockade, providing a rationale for therapeutic co-targeting PD-1 and stromal elements.
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影响因子：
45.3
作者：
Massard, Christophe;Gordon, Michael S.;Segal, Neil H.
通讯作者：
Segal, Neil H.
DOI：
10.1158/1078-0432.ccr-15-1434
发表时间：
2016-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lou Y;Diao L;Cuentas ER;Denning WL;Chen L;Fan YH;Byers LA;Wang J;Papadimitrakopoulou VA;Behrens C;Rodriguez JC;Hwu P;Wistuba II;Heymach JV;Gibbons DL
通讯作者：
Gibbons DL
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS
影响因子：
5.8
作者：
Gaujoux, Renaud;Seoighe, Cathal
通讯作者：
Seoighe, Cathal