Bladder Cancer Immunotherapy Response may be Predicted by Genetics

Keith Syson Chan, Ph.D., translational scientist, professor of Pathology and co-author of the study, said, “It has proven very effective against melanoma and revolutionized lung cancer treatment. Bladder cancer is considered one of the more responsive tumor types, but still has just a 25% durable response rate, so improvement is still needed.”

When a tumor triggers a host immune response, it is referred to as a ‘hot’ tumour because immune cells frequently invade the tumor’s interior. On the other hand, certain cancers, termed as ‘cool’ tumors, prevent immune cells from penetrating.

A gene named discoidin domain receptor tyrosine kinase 2 (DDR2) was linked in a previous work by Theodorescu to anti-PD-1 resistance in animal models of several tumor types. This new study used human cancer data sets in distinct tumor types in a partnership between cancer biologists and bioinformatics specialists to better analyze the DDR gene family.

As the study’s first author, Sungyong You, Ph.D., a computational biologist with experience in urologic oncology, examined information from The Cancer Genome Atlas programme, a freely accessible database with details on hundreds of cancer samples, to examine the relationship between the expression of the related gene DDR1 and the host immune response to a tumor using bladder cancer as a model. He also studied the correlation between the genes controlled by DDR2 and DDR1 (also known as gene signatures). Then, he examined patient data from IMvigor 210, a clinical trial that assessed the effectiveness of immunotherapy in treating bladder cancer, to see whether these outcomes related to the expression of DDR2 and DDR1 or their associated gene profiles.

The investigators concluded

First, while belonging to the same gene family, the DDR1 and DDR2 genes have extremely distinct impacts on cancers. DDR2 expression is often low in tumors with high DDR1 expression and vice versa. Furthermore, while high DDR2 tumors are ‘hot’, high DDR1 tumors are ‘coo”.

Researchers also discovered four distinct gene profiles strongly correlated with tumor response to immunotherapy and were controlled by DDR1 and DDR2. These genetic markers were also studied in other collections of patient data from various cancer types that were made publicly available.

“We found that these gene signatures were clearly associated with response to immunotherapy in bladder cancer and lung cancer tumors in multiple patient groups. We also evaluated the signatures in publicly available data on melanoma, glioblastoma and blood cancers, with similar results,” said You.

“The next step is to validate these signatures in a prospective clinical trial. This could yield new tools that allow clinicians to determine pre-treatment whether given patients will likely respond to anti-PD-1/PD-L1 therapy. They can then proceed with anti-PD-1/PD-L1 therapy for those patients who will derive the most benefit and offer alternative therapies for patients not likely to respond, improving outcomes for all,” said Theodorescu.

Source: Eurekalert