Genomics-guided tool helps guide immunotherapy choices for advanced kidney cancers

A study led by Roswell Park Comprehensive Cancer Center helps 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 advanced kidney cancers.

The collaborative work by a team of immunologists and urologists was published in the journal Cancer Cell.

Jason Muhitch, Ph.D., Associate Professor and Co-Chair of the Genitourinary Translational Research Group in the Department of Immunology at Roswell Park, and Eric Kauffman, MD, Associate Professor of Oncology in the Departments of Urology and Cancer Genetics & Genomics, are senior authors of the study.

Nicholas Salgia, an MD/Ph.D. 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 the first author.

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 in the late stages, is resistant to most anti-cancer therapies, a type of immunotherapy called immune checkpoint blockade (ICB) has proved to be the exception.

ICB 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 sarcomatoid renal cell carcinomas to checkpoint inhibition to better understand what can make kidney tumors more susceptible to immunotherapy in general,” says Salgia.

Armed with information about tumors from more than 3,000 kidney cancer patients, he and his colleagues used state-of-the-art technologies to explore the inner workings of sarcomatoid RCC tumors.

Using single-cell RNA sequencing of tumor cells, the team discovered that these kidney tumors are fortified with a robust immune system. Compared with clear cell RCC tumors, sarcomatoid RCC 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 clear cell RCC tumors, sarcomatoid RCC tumors contain more “immune hubs” called tertiary lymphoid structures, where immune cells communicate with each other.

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 (GDS) to meet that need.

“This tool holds promise as a biomarker for guiding decisions in advanced kidney cancer,” says 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.”

Adds Dr. Kauffman, who is also a staff physician at Roswell Park, specializing in the care of kidney cancer patients. “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 Roswell Park plans to initiate a prospective study to assess the impact of this gene signature for predicting immunotherapy response in kidney cancer patients who have undergone surgical removal of a kidney tumor.

Provided by
Roswell Park Comprehensive Cancer Center

A study led by Roswell Park Comprehensive Cancer Center helps 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 advanced kidney cancers.

The collaborative work by a team of immunologists and urologists was published in the journal Cancer Cell.

Jason Muhitch, Ph.D., Associate Professor and Co-Chair of the Genitourinary Translational Research Group in the Department of Immunology at Roswell Park, and Eric Kauffman, MD, Associate Professor of Oncology in the Departments of Urology and Cancer Genetics & Genomics, are senior authors of the study.

Nicholas Salgia, an MD/Ph.D. 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 the first author.

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 in the late stages, is resistant to most anti-cancer therapies, a type of immunotherapy called immune checkpoint blockade (ICB) has proved to be the exception.

ICB 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 sarcomatoid renal cell carcinomas to checkpoint inhibition to better understand what can make kidney tumors more susceptible to immunotherapy in general,” says Salgia.

Armed with information about tumors from more than 3,000 kidney cancer patients, he and his colleagues used state-of-the-art technologies to explore the inner workings of sarcomatoid RCC tumors.

Using single-cell RNA sequencing of tumor cells, the team discovered that these kidney tumors are fortified with a robust immune system. Compared with clear cell RCC tumors, sarcomatoid RCC 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 clear cell RCC tumors, sarcomatoid RCC tumors contain more “immune hubs” called tertiary lymphoid structures, where immune cells communicate with each other.

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 (GDS) to meet that need.

“This tool holds promise as a biomarker for guiding decisions in advanced kidney cancer,” says 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.”

Adds Dr. Kauffman, who is also a staff physician at Roswell Park, specializing in the care of kidney cancer patients. “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 Roswell Park plans to initiate a prospective study to assess the impact of this gene signature for predicting immunotherapy response in kidney cancer patients who have undergone surgical removal of a kidney tumor.

Provided by
Roswell Park Comprehensive Cancer Center