Predicting Immunotherapy Resistance in Bladder Cancer

New research from the Mount Sinai Health System identified potential genetic and cellular predictors of immunotherapy response to treatment for metastatic bladder cancer.

The investigators aimed to identify the molecular and cellular features linked to resistance to PD-1/PD-L1 blockade for treating metastatic urothelial cancer. Researchers analyzed bulk RNA sequencing data from two clinical trials of immunotherapeutic agents targeting PD-1/PD-L1. These data were compared to generated single-cell RNA sequencing data from bladder cancer specimens.

The team was able to identify two gene signatures associated with immunotherapy resistance: one which triggered an adaptive immunity response and was associated with improved outcomes, and a second that was associated with pro-tumorigenic inflammation and treatment resistance. The ratio of adaptive immunity to pro-tumorigenic inflammation was titled “2IR” by the researchers and was found to be predictive of clinical outcomes.

“If the tumor microenvironment is weighted more toward adaptive immunity, there’s a better chance of positive outcomes from immunotherapy,” said senior author Matthew Galsky, MD, Professor of Medicine at the Icahn School of Medicine at Mount Sinai, via a press release.  “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.”

In addition, the researchers also identified a specific subset of white blood cells, myeloid phagocytic cells, that triggered this pro-tumorigenic inflammation, which may serve as prospective therapeutic targets for novel agents to combat this resistance mechanism.

“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,” said Dr. Galsky.

Findings from this study were published in Clinical Cancer Research.