Results from a recent study may help to explain why a rare and hyper-aggressive subtype of kidney cancer is susceptible to immunotherapy—information that helped researchers create a first-of-its-kind tool to guide treatment decisions for patients with advanced kidney cancers. The collaborative work by a team of immunologists and urologists was published by Salgia et al in Cancer Cell.
Jason Muhitch, PhD, Associate Professor and Co-Chair of the Genitourinary Translational Research Group in the Department of Immunology at Roswell Park Comprehensive Cancer Center, and Eric Kauffman, MD, Associate Professor of Oncology in the Departments of Urology and Cancer Genetics & Genomics at Roswell Park, are senior authors of the study. Nicholas Salgia, an MD/PhD candidate through the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, who completed his thesis work in the lab of Dr. Muhitch, is first author.
Sarcomatoid RCC
The new insights arose from observations about sarcomatoid renal cell carcinoma (sRCC), an aggressive subtype comprising 5% of all cases of kidney cancer. While this subtype, typically diagnosed at a late stage, is resistant to most anticancer therapies, immune checkpoint blockade has proved to be the exception. Immune checkpoint blockade approaches have greatly improved survival among patients with both sRCC and the most common type of kidney cancer, clear cell renal cell carcinoma (ccRCC)—but patients with sRCC have benefited disproportionately.
“We focused on the unexpected responsiveness of sRCCs to checkpoint inhibition to better understand what can make kidney tumors more susceptible to immunotherapy in general,” said Mr. Salgia. Armed with information about tumors from more than 3,000 patients with kidney cancer, he and his colleagues used state-of-the-art technologies to explore the inner workings of sRCC tumors.
Key Findings
Using single-cell RNA sequencing of tumor cells, the team discovered that these kidney tumors are fortified with a robust immune system. Compared with ccRCC tumors, sRCC tumors contain a higher volume of plasma cells, which play a key role in the production of antibodies that can tag cancer cells for eventual destruction. The scientists also found that, compared with ccRCC tumors, sRCC tumors contain more “immune hubs” called tertiary lymphoid structures, where immune cells communicate with each other.
Creation of a Novel Tool
While advanced kidney cancers are typically treated with either immunotherapy or targeted therapy, until now, there has been no reliable tool for determining which patients would benefit most from one treatment or the other. The research team created a tool called a genomic dedifferentiation signature to meet that need.
“This tool holds promise as a biomarker for guiding decisions in advanced kidney cancer,” said Dr. Muhitch. “We identified a set of genes that were increased in these aggressive tumors, and from this set of genes, we created a novel gene signature that can identify patients with aggressive disease who are also primed to respond to immune-based cancer therapy.”
Added Dr. Kauffman, who is also a staff physician at Roswell Park specializing in the care of patients with kidney cancer, “This signature may expose an Achilles’ heel of sarcomatoid kidney cancers that makes them more vulnerable to immunotherapy treatment. 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.”
To apply and develop the findings from this retrospective genomic analysis, within the next year, the research team plans to initiate a prospective study to assess the impact of this gene signature for predicting immunotherapy response in patients with kidney cancer patients who have undergone nephrectomy.
Disclosure: The research team included scientists from the Translational Genomics Research Institute in Arizona, City of Hope Comprehensive Cancer Center, and Yale University School of Medicine. The work was funded in part by the National Cancer Institute and donations to the Roswell Park Alliance Foundation and Roswell Park Friends of Urology. For full disclosures of the study authors, visit cell.com.
