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.
Highlights
Bladder cancer is the ninth most common malignancy worldwide and the fifth most common cancer in Europe and the United States, with the highest incidence found in southern European countries [1]
We identified a median of 58 predicted neoantigens in the 36 tumors, which were verified by RNAsequencing data (Table S7)
Our results demonstrated that Bacillus Calmette–Guérin (BCG)-treated non-muscle-invasive bladder cancer (NMIBC) patients underwent dynamic clonal evolution throughout the progression of the tumor, with significant genetic and immune editing during BCG treatment
Summary
Bladder cancer is the ninth most common malignancy worldwide and the fifth most common cancer in Europe and the United States, with the highest incidence found in southern European countries [1]. Intravesical Bacillus Calmette–Guérin (BCG) instillation is the “gold standard” adjuvant treatment after transurethral resection of the bladder tumors in high-risk NMIBC patients. BCG immunotherapy has markedly improved the outcome of NMIBC, the response rates to BCG vary from 32.6% to 42.1%; in addition, the progression rates range from 9.5% to 13.4% and are dependent on a multitude of factors [4]. Accurate prediction of treatment response before BCG instillation will be valuable for selecting an appropriate therapeutic modality. Blood biomarkers, such as lymphocyte, neutrophil, and platelet counts, reflect the balance of host inflammatory and immune status and are an established prognostic factor in bladder cancer [7]. 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. The response rates to BCG vary widely and are dependent on a multitude of factors
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