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Macrophage Subpopulation May Predict Kidney Cancer Recurrence, Serve as Drug Target

NEW YORK — Researchers have uncovered a population of macrophages that appears to be more common among kidney cancers that recur than those that don't, suggesting signatures associated with these cells could also be used as a prognostic marker.

While primary clear cell renal carcinoma can be treated surgically, about 40 percent of patients will experience relapse and develop metastases, and metastatic clear cell renal carcinoma has a five-year survival rate of only 10 percent.

A team led by researchers at Columbia University combined single-cell RNA sequencing with an algorithm to gauge single-cell protein activity to identify and characterize the immune cells that infiltrate ccRCC. As they reported on Thursday in the journal Cell, the researchers analyzed more than 200,000 tumor and normal cells from 11 patients with ccRCC. They found that patients whose tumors had increased numbers of macrophages with upregulated TREM2, APOE, and C1Q were more likely to experience recurrence.

"Our findings suggest that the presence of these cells could be used to identify patients at high risk of disease recurrence after surgery who may be candidates for more aggressive therapy," co-senior author Charles Drake, an adjunct professor of medicine at Columbia University, said in a statement.

Drake and his colleagues sought to develop an atlas of the immune cells that infiltrate ccRCC by conducting single-cell RNA sequencing of hematopoietic and non-hematopoietic cells from tumor and normal adjacent tissue from 11 patients who had not undergone any treatment. Gene expression-based clustering could separate these cells into populations of, for instance, CD4 and CD8 lymphocytes, natural killer cells, or macrophages.

However, due to gene dropout in which single-cell RNA sequencing misses mRNAs that are expressed at low levels, this approach did not capture all known cellular markers and immune cell subpopulations.

To address this issue, the researchers used the meta-VIPER algorithm, which is derived from the VIPER algorithm, that predicts which genes are active in a sample based on the expression of related genes. Through this, the researchers estimated they could accurately detect the activity of between 70 percent and 80 percent of all regulatory genes in each cell.

Following the meta-VIPER-based analysis, they could then identify additional subpopulations of immune cells.

For instance, within the samples, they noticed a subpopulation of macrophages that were tumor specific and marked by upregulation of the TREM2, APOE, and C1Q genes. In a separate cohort of 157 patients, the researchers confirmed the link between the expression of those genes and tumors. They also noted that these markers were associated with a shorter time to relapse among patients, suggesting that they could serve as a signature for clear cell renal carcinoma recurrence.

The researchers additionally found that these macrophages may directly interact with tumor cells and could represent a potential target for therapeutics.

"These data raise the intriguing possibility that these macrophages are not just markers of more risky disease but may actually cause the disease to recur and progress," co-first author Aleksandar Obradovic, an MD/PhD student at Columbia, said in a statement, "and that targeting these cells could improve clinical outcomes."

The researchers added that their approach, combining single-cell sequencing and the VIPER algorithm, could be used to interrogate other types of cancer as well.