Tumor splicing burden predicts treatment response in kidney cancer

Researchers at City of Hope^® and TGen (part of City of Hope) have identified a significant correlation between a tumor's "splicing burden" and its clinical response to treatment for metastatic renal cell carcinoma (mRCC).

City of Hope is one of the largest and most advanced cancer research and treatment organizations in the United States, with its National Medical Center ranked among the nation's top cancer centers by U.S. News & World Report.

In a study published today in the Journal for ImmunoTherapy of Cancer, researchers demonstrated that patients whose tumor tissue exhibits a high frequency of aberrant gene splicing are more likely to respond to therapy compared to those with fewer aberrant splicing events. These findings suggest that errors present within a tumor's transcriptomic landscape may provide a much-needed predictive framework for personalizing treatment for patients with metastatic kidney cancer.

While the natural process of splicing prepares mature mRNA for protein production, it often goes awry in malignant cells. These aberrant splicing events were previously known to drive cancer progression, but their role as a predictive tool in mRCC treatment remained largely untapped.

The role of aberrant splicing in mRCC was underexplored until this study. The more precisely we understand these splicing disruptions, the more directly we can inform therapeutic strategies that restore function for mRCC patients."

Patrick Pirrotte, Ph.D., associate professor in TGen's Early Detection and Prevention Division, director of the Integrated Mass Spectrometry Shared Resource at TGen and City of Hope, and senior author of the paper

The research team performed RNA sequencing on tumor specimens from 101 mRCC patients. By analyzing the transcriptome, they sought to fill a critical gap in current diagnostics.

"There aren't many prognostic or predictive biomarkers in the kidney cancer space," said Benjamin Mercier, B.S., a clinical research coordinator at City of Hope and first author on the study. "Our objective was to determine if we can identify predictive biomarkers from the transcriptome of these tumors."

The data revealed hundreds of distinct splicing events that differentiated "responders," individuals whose treatment demonstrated clinical benefit through obvious tumor shrinkage or stable disease for at least six months, from "non-responders." Specifically, 13 unique splicing events were highly prevalent in those who successfully responded to immunotherapies and tyrosine kinase inhibitors. The results suggest that these mistakes help trigger the immune system by creating new or malformed proteins that flag the cancer cell so the body knows to attack it.

"And that is extremely important when you are trying to use or activate the immune system," Pirrotte explains. "The tumor cells can only be recognized if they're producing a signature that makes them different from normal cells." Tumors with a high splicing burden showed signs of robust adaptive immune activation, suggesting the body may already be "primed" to attack the cancer if given the right therapeutic nudge.

For clinicians, these findings represent more than just molecular data; they could someday provide biomarkers to guide personalized therapy options for patients.

"By understanding how abnormal gene-splicing affects treatment, we're opening the door to innovative therapies that reshape patient outcomes and redefine what effective cancer treatment can look like," says Sumanta Pal, M.D., co-director of the Kidney Cancer Program at City of Hope and a senior author on the study.

This work adds to a growing body of evidence from Pirrotte and his colleagues suggesting that splicing events could serve as universal biomarkers across various malignancies, including ovarian cancer and sarcomatoid renal cell carcinoma. By decoding the chaos of the cancer transcriptome, researchers are moving closer to a future where aberrant splicing can be reliably harnessed to guide the next generation of cancer care.