Newswise – LOS ANGELES (August 3, 2022) — Cedars-Sinai Cancer researchers have identified genetic signatures that could predict whether tumors in patients with bladder and other cancers will respond to immunotherapy. Their findings, published today in the peer-reviewed Journal of the National Cancer Institute, could one day help guide doctors to the most effective treatments for cancer patients.
“Our work indicates that these genetic signatures can be very valuable in predicting immunotherapy response in patients with bladder cancer, but also other types of tumors,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer , the PHASE ONE Foundation. Distinguished Chair and lead author of the study. “We will continue to investigate these biomarkers with the goal of bringing them to clinical use and improving patient outcomes.”
Over the past five years, anti-PD-1/PD-L1 therapy, a type of cancer immunotherapy that paves the way for the body’s immune system to attack tumor cells, has proven effective against many type of cancer, according to Keith Syson Chan, PhD, translational scientist, professor of Pathology and co-author of the study.
“It has proven to be very effective against melanoma and revolutionized the treatment of lung cancer,” Chan said. “Bladder cancer is considered one of the most sensitive types of tumors, but it still has a durable response rate of 25%, so there is still room for improvement.”
When a tumor provokes an immune reaction from the host, immune cells often infiltrate the core of the tumor and scientists call it a “hot” tumor. Some tumors, on the other hand, prevent immune cells from infiltrating and are known as “cold” tumors.
An earlier study by Theodorescu implicated a gene, called discoidin domain receptor tyrosine kinase 2 (DDR2), in contributing to anti-PD-1 resistance in animal models in various tumor types. In a collaboration between cancer biologists and bioinformatics researchers, this new study further investigated the DDR gene family using human cancer data sets in various tumor types.
Sungyong You, PhD, a computational biologist with expertise in urologic oncology and first author of the study, analyzed data from The Cancer Genome Atlas program, a publicly available database of information on hundreds of cancer samples, to see how the ‘expression of DDR2 and the related ones. the DDR1 gene was correlated with the host’s immune response to a tumor using bladder cancer as a model. It also looked at how DDR2- and DDR1-regulated genes correlated (i.e., gene signatures). He then examined data from patients in IMvigor 210, a clinical trial that evaluated immunotherapy response in bladder cancer, to see if those responses correlated with DDR2 and DDR1 expression or their related gene signatures .
The researchers came away with two key findings.
First, although the DDR1 and DDR2 genes are members of the same family, they have very different effects on tumors. Tumors with high expression of DDR1 tend to show low expression of DDR2 and vice versa. And high DDR1 tumors are “cold”, while high DDR2 tumors are “hot”.
The researchers also identified four unique gene signatures modulated by DDR1 and DDR2 that were closely associated with tumor response to immunotherapy. They checked these genetic signatures in several additional sets of publicly available patient data across various types of cancer.
“We found that these gene signatures were clearly associated with response to immunotherapy in bladder cancer and lung cancer tumors in several patient groups,” he said. “We also evaluated the signatures in publicly available data on melanoma, glioblastoma and blood cancers, with similar results.”
“The next step is to validate these signatures in a prospective clinical trial,” Theodorescu said. “This could yield new tools that allow clinicians to determine pretreatment whether given patients are likely to respond to anti-PD-1/PD-L1 therapy. They can then proceed with anti-PD-1/PD-L1 therapy to patients who will derive the greatest benefit and provide alternative therapies for patients who do not respond, improving outcomes for all.”
Funding: The study was supported by National Institutes of Health grant numbers CA075115 and CA175397.
Learn more on the Cedars-Sinai Blog: Advances in Bladder Cancer