Background 

About half of all people with non-muscle invasive bladder cancer see their tumors come back even after receiving BCG treatment, which is a common therapy placed directly into the bladder. When this happens, it means that the cancer has become resistant to the treatment and is harder to control. 

What the Study Proposes to Address 

Scientists have discovered that tumors resistant to BCG often have high levels of certain proteins called PD and PDL-1. These proteins can stop the immune system from attacking cancer cells. Drugs that block PD/PDL-1 exist, but they only work well for about 19% of patients. This study uses advanced technology—called spatial transcriptomics and imaging mass cytometry—to take a very detailed look at how cells inside these tumors interact with each other. By understanding this environment more clearly, researchers hope to find new ways to treat BCG-resistant cancers and make immunotherapy work better. 

Why This Research is Important 

This research could help doctors discover why many bladder cancers don’t respond to today’s treatments and what can be done to change that. A deeper look into how these cancer and immune cells behave might lead to new treatments that stop the cancer from coming back. Ultimately, this could improve survival and quality of life for patients whose bladder cancer no longer responds to standard therapies. 

Final Report Summary 

When bladder cancer returns in patients with non-muscle invasive bladder cancer (NMIBC), the immune system is clearly trying to fight it, but in an unbalanced way. The researchers found that a specific immune signal, called IFN-γ, plays a big role in this response. In patients whose cancer does not respond to BCG treatment, the body produces high levels of certain inflammation signals that should help fight cancer—but instead, they seem to backfire. The tumor cells react by creating “shields” that allow them to hide from the immune system, so the body can no longer destroy them effectively. 

The team also discovered that certain molecules called HLA-E and NKG2A are especially important in these resistant tumors. They appear to help the cancer escape the immune attack. Using several advanced scientific tools, the researchers found that these tumor cells gather in areas filled with immune cells, showing how the body keeps trying—and failing—to control the cancer. 

This new understanding has led to a clinical trial called ENHANCE. It will test whether combining two immune-based drugs can help the body better fight high-grade bladder cancer without removing the bladder, giving patients a new hope for treatment. 

Salomé, B., Sfakianos, J. P., Ranti, D., Daza, J., Bieber, C., Charap, A., Hammer, C., Banchereau, R., Farkas, A. M., Ruan, D. F., Izadmehr, S., Geanon, D., Kelly, G., de Real, R. M., Lee, B., Beaumont, K. G., Shroff, S., Wang, Y. A., Wang, Y. C., Thin, T. H., … Horowitz, A. (2022). NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer. Cancer cell, 40(9), 1027–1043.e9. https://doi.org/10.1016/j.ccell.2022.08.005

National Cancer Institute/National Institute of Health/Department of Health and Human Services “HLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancer”, 2023, $3,359,953

National Cancer Institute/National Institute of Health/Department of Health and Human Services ” Identifying novel resistance mechanisms in non-muscle invasive bladder cancer treated with Bacillus Calmette-Guerin (BCG)”, 2023, $451,019

National Institute of Health,”Dissecting Myeloid-Cell mediated Resistance to Immune Checkpoint Blockade in Bladder Cancer”, 2020, $3,488,861

Department of Defense, “Determining the contribution of lineage intermediate tumor cells during progression to t-SCNC”, 2023, $1,521,002

National Cancer Institute/National Institute of Health, “Targeting the Androgen receptor to sensitize Bladder Cancer to Immune Check Point Blockade”, 2024, $434,542

Amir Horowitz, PhD; Icahn School of Medicine at Mount Sinai
Olivier Elemento, PhD; Cornell University