Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response

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

Abstract

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.

Datasets

1. ccRCC - Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response
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Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response
2. normal - Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response
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Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response
3. chRCC - Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response
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Tumor2271 cells
Macro129 cells
vSMC110 cells
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Tcell30 cells
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Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response

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Source data

https://cellxgene.cziscience.com/collections/1df8c90d-d299-4b2e-a54d-a5a80f36e780

Alias names

PMID34099557, PMC8214680

Cite this study

Zhang, Y., Narayanan, S.P., Mannan, R., Raskind, G., Wang, X., Vats, P., Su, F., Hosseini, N., Cao, X., Kumar-Sinha, C. and Ellison, S.J., 2021. Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response. Proceedings of the National Academy of Sciences, 118(24), p.e2103240118. https://doi.org/10.1073/pnas.2103240118