Biology subjects

Choy, B.

Publications and source records attributed to Choy, B..

2 recordsLinked to original sources

bioRxiv2025

Divergent Macrophage-Regulated T cell States Determine Response to Bacillus Calmette-Guerin (BCG) in High-Risk Bladder Cancer

The primary therapy for high-risk bladder cancer (BCa) is repeated instillations of the tuberculosis vaccine, Bacillus Calmette-Guerin (BCG). While BCG decreases the risk of recurrence by more than half, the concerted mechanisms of immune activation from BCG are unknown. Our objective was to investigate how the immune response differs between responders and non-responders to BCG therapy. We performed single-cell RNA-sequencing of isolated immune cells adjacent to high-risk bladders before and after BCG in BCG responders and non-responders. We identify an increase in Th17-like Th1 cells in BCG responders, characterized by greater expression of pro-inflammatory cytokines. Alternatively, non-responders had increased CD8+ T-cell exhaustion and T-regulatory cells. We identify that the primary mechanism of divergent T cell activity is driven by altered polarization and immunosuppressive signaling with myeloid cells. Through a machine-learning-based approach, we identified a Th17-like Th1 cytokines, such as IL17, IL21, and IL26, were predictive of a response, which were then validated in a separate BCG-treated BCa cohort. Together, this suggests that dynamic regulation of myeloid-T cell interactions can be targeted to improve BCG activity.

immunology↗

bioRxiv2024

Genomic and transcriptomic profiling of high-risk bladder cancer reveals diverse molecular and microenvironment ecosystems

Despite surgical resection, rigorous endoscopic surveillance, and immunotherapy with the Bacillus Calmette-Guerin (BCG) vaccine, 30% of high-risk bladder cancers recur, and 10% result in fatal outcomes within two years of diagnosis. The global shortage of BCG underscores the urgent need for alternative or complementary therapeutic strategies. To address this, we integrated transcriptomic profiling and targeted genomic sequencing to identify four consensus intrinsic subtypes of bladder cancer. Initially derived from bulk RNA profiling, these subtypes were further validated at the cellular and tissue-compartment levels using single-cell RNA sequencing and spatial transcriptomics. Notably, we identified a subtype of inflamed tumors with enhanced endogenous retroelement expression and increased commensal bacterial presence, which showed the highest responsiveness to BCG therapy. Additionally, we developed a machine learning-based model incorporating composite molecular features to predict recurrence risk, achieving a high accuracy (AUC = 0.90). Our findings establish a molecular precision framework for bladder cancer and nominate novel therapeutic targets to reduce reliance on BCG immunotherapy.

cancer biology↗