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.
Cell. 2021 May 13 [Epub ahead of print]
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, Charles G Drake
Columbia Center for Translational Immunology (CCTI), Columbia University Irving Medical Center (CUMC), New York, NY 10032, USA; Department of Systems Biology, HICC, New York, NY 10032, USA., Columbia Center for Translational Immunology (CCTI), Columbia University Irving Medical Center (CUMC), New York, NY 10032, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., MD Anderson Cancer Center, Houston, TX, USA., Columbia Center for Translational Immunology (CCTI), Columbia University Irving Medical Center (CUMC), New York, NY 10032, USA., Department of Urology, Herbert Irving Comprehensive Cancer Center (HICC), New York, NY 10032, USA., Department of Systems Biology, HICC, New York, NY 10032, USA., Vanderbilt University Medical Center, Nashville, TN, USA., Department of Urology, Herbert Irving Comprehensive Cancer Center (HICC), New York, NY 10032, USA; HICC, Columbia University, New York, NY, USA., Department of Systems Biology, HICC, New York, NY 10032, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; HICC, Columbia University, New York, NY, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY; Department of Biomedical Informatics, Columbia University, New York, NY, USA; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA; J.P. Sulzberger Columbia Genome Center, New York, NY, USA. Electronic address: ., Columbia Center for Translational Immunology (CCTI), Columbia University Irving Medical Center (CUMC), New York, NY 10032, USA; Department of Urology, Herbert Irving Comprehensive Cancer Center (HICC), New York, NY 10032, USA; HICC, Columbia University, New York, NY, USA. Electronic address: .