A new way to predict positive outcomes of immunotherapy in patients with bladder cancer

Mount Sinai researchers have detected and validated groups of genes linked to immunotherapy resistance in patients with metastatic urothelial cancer of the bladder.

Bladder Cancer. Image Credit: Shidlovski/Shutterstock.com

The researchers revealed gene signatures indicating pro-tumorigenic inflammation and adaptive immunity that were responsible for resistance or sensitivity to immune checkpoint inhibitors—medications that allow the body’s immune system to detect and attack tumor cells. The study was published in the Clinical Cancer Research journal.

These findings enabled us to identify potential biomarkers in patients who are less likely to respond favorably to immune checkpoint inhibitors, as well as new combination therapeutic approaches that might overcome such resistance in those patients.”

Matthew Galsky, MD, Study Senior Author and Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai

These results considerably revealed that the balance between pro-tumorigenic inflammation and adaptive immunity in separate tumor microenvironments—replicated by both these gene signatures—optimally predicted the resistance or response to the immune checkpoint blockade.

The investigators subsequently detected particular cells in the tumor microenvironment related to resistance to the immune checkpoint blockade and identified promising targets for treatments developed to overcome resistance.

For many years, platinum-based chemotherapy has been the routine treatment for metastatic urothelial cancer of the bladder, although the landscape has significantly changed in the recent past with the introduction of PD-1 and PD-L1 immune checkpoint inhibitors.

But this therapeutic innovation has had its limitations: only 20% to 25% of bladder cancer patients respond to therapy, triggering an active search by biomedical researchers for the resistance mechanisms.

Using RNA sequencing data from two clinical trials, and single-cell RNA sequencing data from a cohort of bladder tumors, we identified a subset of genes and immune cells associated with adaptive immunity and improved checkpoint inhibitor outcomes, and a subset associated with pro-tumorigenic inflammation and resistance to PD-1/PD-L1 blockade in patients with urothelial cancer.”

Matthew Galsky, MD, Study Senior Author and Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai

The study is one of the first to apply both bulk sequencing and single-cell RNA sequencing of human bladder tumors to investigate resistance to immunotherapy. While bulk sequencing investigates the combination of genes expressed by each individual cell inside a tumor, single-cell sequencing—a method that has become increasingly significant in cancer studies—targets gene expression by every individual cell, providing an unparalleled understanding of the heterogeneity and complexity of cells continuing tumors.

By this mixture of RNA sequencing, scientists have learned, for instance, that the balance of pro-tumorigenic inflammation and adaptive immunity inside the tumor microenvironment can establish the resistance to PD-1/PD-L1 blockade in urothelial cancer.

Adaptive immunity refers to the body’s capacity to detect and react to certain foreign invaders, whereas pro-tumorigenic inflammation is a counterproductive reaction of the immune system that can eventually drive the growth and development of cancer.

“If the tumor microenvironment is weighted more toward adaptive immunity, there's a better chance of positive outcomes from immunotherapy,” explained Dr. Galsky, who is also an Associate Director of Translational Research and Co-Director of the Bladder Cancer Center of Excellence at The Tisch Cancer Institute.

On the other hand, if the tumor microenvironment is leaning toward pro-tumorigenic inflammation, then PD-1/PD-L1 checkpoint inhibitors alone are unlikely to be successful, and new combination approaches may be needed.”

Matthew Galsky, MD, Study Senior Author and Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai

To quantify that balance, the researchers from Mount Sinai have coined the term “2IR Score.”

From their detailed RNA study, the investigators have not only detected promising biomarkers to treatment resistance, but also a certain subset of white blood cells called myeloid phagocytic cells that are associated with pro-tumorigenic inflammation and, thus, resistance.

In this context, these cells act as potential targets for therapeutic strategies that integrate immunotherapies, like PD-1/PD-L1 blockade with medications developed to overcome the resistance caused by myeloid cells. Such innovative combination approaches are presently being integrated into upcoming clinical trials.

“Our research shows that a specific cellular state of myeloid cells underlying pro-tumorigenic inflammation account for resistance to immune checkpoint blockade in a very large percentage of patients with urothelial bladder cancer. This is an important finding which we believe can lead to a better focus and direction for developing effective combination therapies—and not just for bladder cancer, but other types of tumors, as well,” concluded Dr. Galsky.