Investigators from Cedars-Sinai Cancer have identified genetic signatures that could predict whether tumors in patients with bladder and other cancers will respond to immunotherapy. Their results, published in the peer-reviewed Journal of the National Cancer Institute, could one day help guide clinicians to the most effective treatments for cancer patients.
During 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 proved effective against many cancer types, according to Keith Syson Chan, PhD, a translational scientist, professor of Pathology and co-author of the study.
When a tumor causes a host immune reaction, immune cells usually are able to infiltrate the core of the tumor, and scientists call it a “hot” tumor. Some tumors, on the other hand, block immune cells from infiltrating and are known as “cold” tumors.
A previous study by Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Foundation Distinguished Chair and senior author of the study, implicated a gene—called discoidin domain receptor tyrosine kinase 2 (DDR2)—in contributing to anti-PD-1 resistance in animal models in several 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 with information on hundreds of cancer samples, to look at how expression of DDR2 and related gene DDR1 correlated with the host immune response to a tumor using bladder cancer as a model. He also looked at how genes regulated by DDR2 and DDR1 (i.e., gene signatures) correlated. He then looked at patient data from IMvigor 210, a clinical trial that evaluated immunotherapy response in bladder cancer, to see if these responses correlated with DDR2 and DDR1 expression or their related gene signatures.
The investigators came away with two key findings.
First, while 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 exhibit low expression of DDR2 and vice versa. And high DDR1 tumors are “cold,” while high DDR2 tumors are “hot.”
Investigators 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 multiple cancer types.