Biomarkers Could Predict Patients’ Response to Bladder Cancer Therapy

Researchers at Northwestern Medicine have identified immune system markers that may help predict who responds to BCG bladder cancer therapy and who does not. The Journal of Clinical Investigation published the findings. 

The study centers on Bacillus Calmette-Guérin (BCG) for non-muscle-invasive bladder cancer, a cancer affecting the bladder lining, and why the therapy fails for some patients. What determines whether BCG succeeds or fails for any given patient has never been fully explained. BCG functions by exposing the body to a weakened form of bacteria, triggering the immune system to mount a response. 

Despite its long history as a front-line treatment, researchers have remained uncertain about why some patients benefit significantly while others do not. To probe this, the team used single-cell RNA sequencing to examine immune cells drawn from bladder tissue and the circulation, grouping patients by whether their treatment worked. 

Among those who responded, a particular cell type stood out: Th17-like Th1 cells appeared in substantially higher numbers. These are characterized by a strong inflammatory profile that releases cytokines, the chemical signals that activate tumor-fighting immune activity. 

Non-responders had more exhausted CD8+ T-cells, a type with diminished cancer-killing capacity, and elevated regulatory T-cells, which work to hold the immune response in check. Cumulatively, those cell types generate conditions in which cancer continues to advance even when therapy is underway. 

The study also identified myeloid cells as a key variable in how treatment outcomes play out. In responders, the same myeloid cells appeared to steer T-cells toward tumor-fighting behavior. Non-responders had the reverse experience, with those same myeloid cells suppressing rather than activating the immune response. 

Senior study author and Professor of Urology and Biochemistry and Molecular Genetics Joshua Meeks described the link between bladder macrophages and T-cells as the pivotal factor in whether the therapy takes hold. He noted that non-responders showed more suppressive signaling, while patients with good outcomes displayed stronger inflammatory activity. 

The team applied machine learning to determine which of the observed features most reliably predicted outcomes. Cytokines tied to the Th17-like Th1 cell population proved to be the clearest predictors of which patients would respond. Validation against an independent cohort reinforced the case that these markers could eventually identify likely responders before treatment begins. 

The authors note that further work is needed before the markers enter routine clinical practice. Prior work from the team mapped tumor characteristics, Meeks noted, and this study identifies individual immune makeup as an equally critical factor. The next research phase will ask whether the immune patterns seen in responders can be deliberately induced in non-responding patients. 

Weiguo Cui, a professor of Pathology at Northwestern, was a co-author, and he and Meeks noted the findings represent a step toward personalizing treatment decisions in bladder cancer based on immune profile. 

With more work being done by enterprises like Calidi Biotherapeutics Inc. (NYSE American: CLDI) to further refine immunotherapy against different cancers, we could soon see the efficacy rates of these treatments reaching levels that are currently a distant dream. 

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