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Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages

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

Online: https://www.cell.com/cell/abstract/S0092-8674(21)00573-0

Issue: Cell. 2021 May 27;184(11):2988-3005.e16.


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.