Novel Gene Signature Predicts Immunotherapy Response in Advanced Kidney Cancers

Resistant to most therapies, it has shown unusually strong responses to immune checkpoint blockade (ICB), a form of immunotherapy. Researchers have now identified biological features underlying this responsiveness and developed a first-of-its-kind tool to guide treatment selection for advanced kidney cancers, paving the way for future tests to help better manage this disease.

A collaborative team of immunologists and urologists from Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA) led a study using data from over 3,000 kidney cancer patients. Their work focused on single-cell RNA sequencing of tumor cells to explore why sRCC responds better to immunotherapy than clear cell renal cell carcinoma (ccRCC). The analysis revealed key immune system differences that could be used to predict treatment outcomes.

Published in Cancer Cell, the research found that sRCC tumors contain more plasma cells, which produce antibodies to target cancer cells, and more tertiary lymphoid structures, immune hubs where cells coordinate attacks. These features indicate a more active tumor immune environment compared to ccRCC, explaining the stronger ICB response.

From these findings, the researchers created the genomic dedifferentiation signature (GDS), a novel gene signature derived from genes elevated in aggressive kidney tumors. GDS can identify patients likely to respond to immune-based cancer therapy, providing a potential biomarker to guide the choice between immunotherapy and targeted therapy.

This tool could help optimize treatment strategies for advanced kidney cancers and may have applications beyond sRCC. Within the next year, the research team plans a prospective study to evaluate GDS in predicting immunotherapy response in patients who have undergone surgical removal of kidney tumors.

"This signature may expose an Achilles’ heel of sarcomatoid kidney cancers that makes them more vulnerable to immunotherapy treatment," said Eric Kauffman, MD, one of the senior authors of the study. “Our study lays the groundwork for developing future tests to help us better manage this disease, and its implications may also be applicable to other types of kidney cancer.”

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Roswell Park Comprehensive Cancer Center