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Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2103240118
Yuping Zhang, Sathiya P. Narayanan, Rahul Mannan, Gregory Raskind, Xiaoming Wang, Pankaj Vats, Fengyun Su, Noshad Hosseini, Xuhong Cao, Chandan Kumar-Sinha, Stephanie J. Ellison, Thomas J. Giordano, Todd M. Morgan, Sethuramasundaram Pitchiaya, Ajjai Alva, Rohit Mehra, Marcin Cieslik, Saravana M. Dhanasekaran, Arul M. Chinnaiyan

Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.



中文翻译:

肾细胞癌的单细胞分析揭示了对肿瘤微环境、细胞起源和治疗反应的见解 [医学科学]

肾细胞癌 (RCC) 的不同亚型显示出广泛的组织形态学、蛋白质基因组学改变、免疫细胞浸润模式和临床行为。描绘不同 RCC 亚型的起源细胞将提供对其不同病理生物学的机械见解。在这里,我们采用单细胞 RNA 测序 (scRNA-seq) 来开发良性和恶性肾细胞图谱。使用在该细胞图谱上训练的随机森林模型,我们预测了 10 多种 RCC 亚型的假定起源细胞。scRNA-seq 还揭示了肾癌最常见亚型透明细胞 RCC (ccRCC) 中肿瘤微环境的几个属性。我们阐明了肿瘤上皮细胞在促进免疫细胞浸润方面的积极作用,这可能解释了为什么 ccRCC 对免疫检查点抑制剂有反应,尽管新抗原负担较低。此外,我们表征了高内皮细胞类型与 ccRCC 中对免疫疗法缺乏反应之间的关联。总之,这些对良性肾脏和 RCC 的单细胞分析提供了对 RCC 亚型的假定起源细胞的深入了解,并突出了肿瘤微环境在影响 ccRCC 生物学和治疗反应方面的重要作用。

更新日期:2021-06-08
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