Background 

Immunotherapy is a type of treatment that helps the body’s immune system fight cancer. It has changed how doctors treat bladder cancer, and is currently FDA approved for both localized bladder cancer and for tumors that have spread beyond the bladder. To use a car analogy, instead of “accelerating” the immune system by directly stimulating it, immunotherapy works to take the “brake” off the immune system in order to allow it to attack the cancer.   

However, not all patients benefit. Even with strategies that combine immunotherapy with another drug called enfortumab vedotin, about 50% of patients with bladder cancer that has metastasized will die within 32 months.  Moreover, even with treatment in patients with localized bladder cancer, the disease may return, and it may spread to other organs. This shows that we need a deeper understanding of why immunotherapy does not work optimally in some patients, in order to improve. 

What This Research Proposes to Address 

This project examined the role of B cells in bladder cancer.  B cells are immune cells that, depending on many factors, can either stimulate an immune response to fight a patient’s cancer, or block an immune response, which would protect the cancer. Published data suggests that B cells facilitate the response to immunotherapy by stimulating the immune system. However, our preliminary data, using mouse models of bladder cancer, suggested that B cells may facilitate tumor growth. The goal of this project was to further study B cells to try to better determine in what settings B cells may be beneficial and harmful.   

Why This Research Is Important 

If scientists can identify the helpful and harmful characteristics of B cells, they can design new therapies that would accentuate the anti-cancer properties of B cells while inhibiting the pro-cancer features. This would help immunotherapy work more effectively, by improving the ability of these drugs to kill the cancer.     

Ultimately, the goal is to prevent the tumor from spreading in patients with high-risk bladder cancer, and to improve survival for those with advanced disease. By focusing on B cells, this research opens up a new path for better, more precise treatments that could save lives. 

Final Report Summary

Bladder cancer that has spread, called metastatic bladder cancer, is very difficult to treat.  Even with recently FDA approved strategies, about half of patients with metastatic bladder cancer will die within 32 months. One reason for this is that the bladder cancer can trick the body’s immune system into helping the tumor grow instead of fighting it. Researchers want to understand how this happens so they can find ways to reprogram the immune system to attack the cancer. 

This study examined a type of cell in the immune system, called a B cell, and its role in bladder cancer. B cells can either stimulate the immune system to fight cancer, or in some cases, suppress the immune system and facilitate cancer growth. The team examined data from a clinical trial of patients who had metastatic bladder cancer who received treatment with immunotherapy. They found that patients who had both high levels of B cells and another type of immune cell, called CD8+ T cells, in the tumor lived longer after immunotherapy. This phenomenon was seen primarily in men, but not women. However, patients whose tumors had high abundance of B cells, but few CD8+ T cells, did not live as long. This suggests that not all B cells act the same, and whether they are helpful or harmful may depend on the presence of other immune cells. This work is published in European Urology Oncology (Aragaki A et al. 2022;5(3):338-346). 

The researchers have extended the above work to explore the role of B cells in patients who have bladder cancer that has been removed via cystectomy, but where patients are at high risk for recurrence. They have also created new mouse models of bladder cancer to study B cells more closely. Their goal is to modulate the B cell population to eliminate the B cells that facilitate tumor growth, while maintaining the B cells that fight cancer. 

Aragaki, A. K., Jing, Y., Hoffman-Censits, J., Choi, W., Hahn, N. M., Trock, B. J., McConkey, D. J., & Johnson, B. A. (2022). Gender-specific Stratification of Survival Following Immune Checkpoint Inhibitor Therapy Based on Intratumoral Expression of a B cell Gene Signature. European Urology Oncology, 5(3), 338–346. https://doi.org/10.1016/j.euo.2021.07.003

None Reported as of August 2025

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