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Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages (Non-hematopoietic - VIPER-based clustering)

Aleksandar Obradovic, Nivedita Chowdhury, Scott M. Haake, Casey Ager, Vinson Wang, Lukas Vlahos, Xinzheng V. Guo, David H. Aggen, W. Kimryn Rathmell, Eric Jonasch, Joyce E. Johnson, Marc Roth, Kathryn E. Beckermann, Brian I. Rini, James McKiernan, Andrea Califano, and Charles G. Drake

Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target. Keywords: kidney, renal, cancer, tumor

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Species: human
Number of cells: 19781
Number of downloads: 4
Study size: 472MB
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Clear cell renal carcinoma