The functional status of immune cells in the tumor microenvironment and tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle-invasive bladder cancer (NMIBC).
To characterize molecular correlates of post-BCG high-grade (HG) recurrence using multiomics analysis.
Patients with BCG-treated NMIBC (n = 156) were included in the study. Metachronous tumors were analyzed using RNA sequencing (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for immuno-oncology-related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187).
The primary endpoint was post-BCG HG recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher's exact tests were used for analyses.
BCG induced activation of the immune system regardless of clinical response; however, immunoinhibitory proteins were observed in the urine of patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients with post-BCG T-cell exhaustion had high expression of genes related to cell division and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors was associated with worse post-BCG HG recurrence-free survival (HGRFS; p = 0.002). This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors (UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p = 0.018). The retrospective design and partial overlap for analyses are study limitations.
Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor subtype and pre-BCG tumor characteristics may identify patients at high risk of post-BCG HG recurrence. Urinary measurements have potential for real-time assessment of treatment response.
A dysfunctional immune response to bacillus Calmette-Guérin (BCG) therapy may explain high-grade recurrences of bladder cancer.
European urology. 2022 Oct 06 [Epub ahead of print]
Trine Strandgaard, Sia Viborg Lindskrog, Iver Nordentoft, Emil Christensen, Karin Birkenkamp-Demtröder, Tine Ginnerup Andreasen, Philippe Lamy, Asbjørn Kjær, Daniel Ranti, Yuanshuo Alice Wang, Christine Bieber, Frederik Prip, Julie Rasmussen, Torben Steiniche, Nicolai Birkbak, John Sfakianos, Amir Horowitz, Jørgen Bjerggaard Jensen, Lars Dyrskjøt
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark., Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Urology, Aarhus University Hospital, Aarhus, Denmark., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/36210217