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

Abstract

BackgroundBacillus 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.MethodsWe performed a systematic discovery by analyzing the whole exome sequence, expression profile, and immune repertoire sequence of treatment-naive and 5-year time-serial relapsed tumors from 24 NMIBC patients.ResultsBCG therapy showed bidirectional effects on tumor evolution and immune checkpoint landscape, along with a significant reduction of the 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 that the combination of immune checkpoint with BCG treatment may be an effective strategy to treat NMIBC. TCR sequencing revealed treatment-associated changes in the T-cell repertoire in the primary and relapsed tumors.ConclusionOur results provide insight into the genomic and immune dynamics of tumor evolution with BCG treatment, suggest new mechanisms of BCG resistance, and inform the development of clinically relevant biomarkers and trials of potential immune checkpoint inhibitor combination therapies.

Innate and Adaptive Responses of Intratumoral Immunotherapy with Endosomal Toll-Like Receptor Agonists

“…BCG, prepared from attenuated strains of Mycobacterium bovis , is the most widely used vaccine worldwide and has been used to prevent tuberculosis for more than a century [ 38 ]. However, oncological clinical trials were only successful against non-muscle-invasive bladder cancer [ 39 ]. MPL, chemically derived from Salmonella minnesota LPS, has been approved by the FDA as a cervical cancer vaccine, thanks to its immunostimulatory activity and lack of toxicity.…”

Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers

“…However, a relatively high rate of BCG failure, as well as the appearance of side effects, emphasize the need for effective alternative treatment strategies, such as ICIs [19]. Recent evidence has demonstrated that BCG treatment leads to changes in the tumor microenvironment, with an increase in genes regulating immune checkpoints and a significant reduction in neoantigens, which suggests the potential effectiveness of combining ICIs with BCG in relapsed NMIBC tumors [20]. Domingos-Pereira and colleagues have characterized the immune cell infiltration in a mouse orthotopic MB49 bladder tumor model.…”