Algorithm Identifies Macrophage Population Associated with Recurrence

Approximately 40% of clear cell renal cell carcinomas (ccRCC) recur and metastasize following surgical resection, and prognostic factors with high predictive value have not been identified; however, some studies have pointed to the tumor microenvironment (TME) as a potential mediator of recurrence. Obradovic, Chowdhury, Haake, and colleagues developed metaVIPER—a new implementation of VIPER, which is an algorithm that enables determination of protein activity from gene expression information—a tool useable with single-cell data. When applied to live cells derived from treatment-naïve resected ccRCCs and adjacent healthy tissue, metaVIPER outperformed traditional expression-based clustering in analyzing the hematopoietic compartment. Specifically, the traditional approach overlooked several known markers of hematopoietic populations as well as relevant cell populations, such as CD8⁺ T cells expressing exhaustion markers, and (unlike metaVIPER) was incapable of segregating the myeloid compartment into three unique subpopulations of monocytes. Importantly, in treatment-naïve patient ccRCC samples, enrichment with a tumor-specific macrophage subpopulation characterized by different expression of markers identified by the metaVIPER analyses—specifically, C1QA/B/C, APOE, and TREM2—was significantly associated with postsurgical disease recurrence. Further, C1Q and TREM2 protein expression appeared by immunohistochemistry analyses to be nearly completely restricted to tumor tissue rather than adjacent healthy tissue, and macrophages expressing all three aforementioned protein markers (C1Q, APOE1, and TREM2) were often located directly adjacent to tumor cells. Deeper investigation specifically pinpointed the presence of tumor-infiltrating C1Q⁺ macrophages as being an independent prognostic marker of recurrence in ccRCC. Altogether, these findings demonstrate the utility of metaVIPER for quantitative determination of protein activity from single-cell RNA-sequencing data and reveal a macrophage subpopulation predictive of recurrence in ccRCC.

Obradovic A, Chowdhury N, Haake SM, Ager C, Wang V, Vlahos L, et al. Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages. Cell 2021;184:2988–3005.

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