A study conducted by Roswell Park Comprehensive Cancer Center sheds light on why an aggressive subtype of kidney cancer responds to immunotherapy, leading to the development of a groundbreaking tool that aids treatment decisions for advanced kidney cancers.
The collaborative effort, involving immunologists and urologists, was published in Cancer Cell.
Cancer CellJason Muhitch, Ph.D., Associate Professor and Co-Chair of the Genitourinary Translational Research Group at Roswell Park's Department of Immunology, along with Eric Kauffman, MD, Associate Professor of Oncology in Urology and Cancer Genetics & Genomics, are senior authors.
Nicholas Salgia, an MD/Ph.D. candidate through the Jacobs School of Medicine at UB who conducted his research in Dr. Muhitch's lab, is the lead author.
The breakthrough originated from observations about sarcomatoid renal cell carcinoma (sRCC), which makes up 5% of all kidney cancers and is typically diagnosed in late stages. While usually resistant to common anti-cancer treatments, immune checkpoint blockade (ICB) immunotherapy has proven effective against sRCC.
ICB therapy has notably improved survival rates for patients with both sRCC and clear cell renal cell carcinoma (ccRCC), the most prevalent type of kidney cancer, with disproportionately high benefits seen in sRCC cases.
"We focused on sarcomatoid renal cell carcinomas' unexpected response to checkpoint inhibitors to understand these tumors' susceptibility to immunotherapy," explains Salgia.
Analyzing data from over 3,000 kidney cancer patients using advanced technologies, the team examined sarcoma RCC tumors in detail.
Using single-cell RNA sequencing, they discovered that sRCC tumors are richly equipped with a robust immune system. Compared to ccRCC tumors, sRCC contains greater quantities of plasma cells, which play critical roles in producing antibodies that mark cancer cells for destruction.
The team also found more "immune hubs" called tertiary lymphoid structures in sRCC tumors where immune cells interact.
Although advanced kidney cancers are normally treated with either immunotherapy or targeted therapy, tools to determine the optimal treatment had been lacking. The researchers created a genomic dedifferentiation signature (GDS) to address this gap.
"This tool may serve as a biomarker for guiding decisions in advanced kidney cancer cases," says Dr. Muhitch.
He continues, "We identified a set of genes increased in these aggressive tumors and used them to create a novel gene signature capable of identifying patients with aggressive disease who are also primed for immune-based therapy."
Dr. Kauffman, who also specializes in the care of kidney cancer patients at Roswell Park, adds that "This signature reveals a vulnerability of sarcomatoid kidney cancers to immunotherapy treatment. Our study sets the foundation for future tests to better manage this disease and could apply to other kidney cancer types as well."
Over the next year, Roswell Park plans to launch a prospective study to evaluate the impact of this gene signature on predicting immunotherapy response in post-surgery kidney cancer patients.