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Single Cell Analyses of Renal Cell Cancers Reveal Insights into Tumor Microenvironment, Cell of Origin, and Therapy Response

ABSTRACT: Single Cell Analyses of Renal Cell Cancers Reveal Insights into Tumor Microenvironment, Cell of Origin, and Therapy Response

PROVIDER: PRJNA667716 | ENA |

REPOSITORIES: ENA

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Single Cell Analyses of Renal Cell Cancers Reveal Insights into Tumor Microenvironment, Cell of Origin, and Therapy Response

Project description:Diverse subtypes of renal cell carcinomas (RCC) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the ontogeny of these malignancies with the identification of cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. With this aim, we performed single cell RNA sequencing (scRNA-seq) analysis of ~30,000 cells dissociated from benign human kidney and renal tumor specimens. The benign renal tissue cell atlas comprised 26 distinct cell clusters representing all known major and minor cell types, as well as two rare proximal tubule cell types (PT-B and PT-C) and one novel entity containing both intercalated and principal cell (IC-PC) phenotypes. In comparison, the tumor cell atlas was comprised of 13 different cell clusters encompassing neoplastic cells and components of the tumor microenvironment. Using a random forest model trained on the scRNA-seq data from benign tubular epithelial cell types, we predicted the putative cell of origin for more than 10 different RCC subtypes.

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Project description: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.

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