Immune cell patterns predict BCG success in high-risk bladder cancer

High-risk bladder cancer is commonly treated with repeated instillations of the tuberculosis vaccine Bacillus Calmette-Guérin (BCG), which cuts the risk of recurrence by more than half for many patients. Despite its widespread use, clinicians still do not fully understand how BCG activates the immune system or why some people respond while others do not. To address this question, a team led by corresponding author Joshua J. Meeks examined immune cells taken from tissue adjacent to high-risk bladders, sampling before and after BCG therapy in patients who responded to treatment and in those who did not. The researchers used single-cell RNA-sequencing to profile individual immune cells and compare the cellular programs and signaling pathways associated with response. By focusing on the local immune environment around the tumor rather than blood alone, the study aimed to reveal which cell types and molecular signals are linked to successful BCG-driven tumor control and which are associated with treatment failure.

Using single-cell RNA-sequencing of isolated immune cells from the bladder region, the investigators compared BCG responders and non-responders before and after treatment. They found that BCG responders showed an increase in Th17-like Th1 cells, a T cell state marked by higher expression of pro-inflammatory cytokines. In contrast, non-responders were enriched for CD8+ T-cell exhaustion and T-regulatory cells, cell states associated with weakened anti-tumor immunity. The team traced the root of these divergent T cell behaviors to changes in myeloid cells: altered polarization and immunosuppressive signaling from macrophages and other myeloid populations appeared to drive whether T cells became inflammatory or suppressed. A machine-learning-based approach identified Th17-like Th1 cytokines, such as IL17, IL21, and IL26, as predictive of a positive response to BCG, and these cytokine signals were validated in a separate BCG-treated BCa cohort.

The findings point to a dynamic interplay between myeloid cells (macrophages and related populations) and T cells as a key determinant of whether BCG will work in an individual patient. If macrophage polarization and myeloid-driven immunosuppression can be shifted toward a state that supports Th17-like Th1 T cells, it may be possible to increase the fraction of patients who benefit from BCG. The identified cytokines IL17, IL21, and IL26 could serve as biomarkers to predict response or as targets for combination strategies aimed at boosting BCG activity. In practical terms, this work suggests paths for developing tests to stratify patients before BCG and for designing therapies that modulate myeloid-T cell interactions to convert non-responders into responders, improving outcomes in high-risk bladder cancer.