Background 

Bladder cancer is one of the most common cancers in the United States. It is the fourth most common cancer in men and the ninth most common in women. Some bladder cancers are “low-grade,” which usually means they are easier to treat, and patients do well. Others are “high-grade,” which are more dangerous and unpredictable. Doctors have learned that not all high-grade bladder cancers are the same. By looking at patterns in the genes of many bladder tumors, researchers discovered two main groups, called “basal” and “luminal.” These groups cannot be told apart by the way the tumors look under the microscope, but only by studying their genes. 

What the Study Proposes to Address 

The researchers built a special tool that uses 47 genes to tell the difference between basal and luminal bladder cancers. They found that basal tumors produce high levels of certain genes linked to inflammation and to shutting down the body’s immune system. Because new medicines have been shown to help patients by blocking these “off switches” in the immune system, the team believes that basal bladder cancers may respond especially well to this type of treatment, called immunotherapy. To test this idea, they plan to carefully study immune cells in human bladder tumors, use advanced gene sequencing to see if these cells attack specific tumor proteins, and try antibody-based therapies in mouse models of bladder cancer. 

Why This Research is Important 

This work is important because it helps explain why some people with bladder cancer may respond better to new immunotherapy drugs than others. By learning which type of bladder cancer a person has—basal or luminal—doctors may be able to choose treatments that are more likely to work for them. This kind of personalized medicine could improve survival, reduce side effects, and give patients with aggressive bladder cancer more hope for effective treatment in the future. 

Final Report Summary

This study looked at how the body’s immune system reacts to aggressive bladder cancer and created new models to better understand what drives these reactions. Some bladder cancers respond well to new treatments that use the immune system to fight cancer, but most do not. Researchers wanted to figure out why this happens. 

Not all high-grade bladder cancers are the same. These cancers can be grouped into different “subtypes,” and each subtype shows different levels of inflammation, or how much the immune system is activated against the tumor. One important discovery was that when a certain factor, called PPARG, is high, the cancer has much lower levels of inflammation.  

To dig deeper, the team created a new laboratory model of bladder cancer that mimics this type of tumor in people. This model, called UPPL, shows similar immune activity and has a mixed response to a common immune therapy, just like human bladder cancers. The team also shared new cancer cell lines with other scientists so the research community can continue building on this work to develop better treatments. 

Saito, R., Smith, C. C., Utsumi, T., Bixby, L. M., Kardos, J., Wobker, S. E., Stewart, K. G., Chai, S., Manocha, U., Byrd, K. M., Damrauer, J. S., Williams, S. E., Vincent, B. G., & Kim, W. Y. (2018). Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy. Cancer research, 78(14), 3954–3968. https://doi.org/10.1158/0008-5472.CAN-18-0173

None Reported as of August 2025

Jonathan Serody, MD, University of North Carolina
Joel Parker, PhD; University of North Carolina