AUTHOR=Su Fei , Liu Ming , Zhang Wei , Tang Min , Zhang Jinsong , Li Hexin , Zou Lihui , Zhang Rui , Liu Yudong , Li Lin , Ma Jie , Zhang Yaqun , Chen Meng , Xiao Fei 

TITLE=Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.842182

DOI=10.3389/fonc.2022.842182

ISSN=2234-943X

ABSTRACT=Background: Bacillus Calmette-Guérin (BCG) is currently the most effective intravesical therapy for non-muscle-invasive bladder cancer (NMIBC) as it can prevent disease recurrence and progression and lower mortality. However, the response rates to BCG vary widely and are dependent on a multitude of factors.
Methods: We performed a systematic discovery by analyzing the whole exome sequence, expression profiling and immune repertoire sequencing of treatment-naïve and 5-year time-serial relapsed tumors from 24 NMIBC patients.
Results:
BCG therapy showed bidirectional effects on tumor evolution and immune checkpoint landscape, along with a significant reduction of percentage of neoantigen burden. In addition, a remarkable proportion of subclonal mutations were unique to the matched pre- or post-treatment tumors, suggesting the presence of BCG-induced and/or spatial heterogeneity. In the relapsed tumors, we identified and validated a shift in the mutational signatures in which mutations associated with aristolochic acid (AA) exposure were enriched, implying AA may be associated with tumor recurrence. Enhanced expressions of immune checkpoint regulation genes were found in the relapsed tumors, suggesting the combination of immune checkpoint with BCG treatment may be an effective strategy to treat NMIBC. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the primary and relapse tumors.
Conclusion:
Our results provide insight into the genomic and immune dynamics of tumor evolution with BCG treatment, suggest new mechanisms of BCG resistance, and inform development of clinically relevant biomarkers and trials of potential immune checkpoint inhibitor combination therapies.