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Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Response to Bacillus Calmette-Guérin Immunotherapy in Bladder
Juwita N Rahmat1, Sin Mun Tham1, Ting Li Ong2
1Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Abstract:
Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2BFL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2BDel/Del and 24.5% with GSTT2BFL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2BDel/Del and 53.8% of GSTT2BFL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2BDel/Del and 50% of GSTT2BFL/FL. GSTT2FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87-16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2BDel/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.
Insights
Glutathione-S-transferase T2B (GSTT2B) deletion is linked to better Bacillus Calmette-Guérin (BCG) treatment response in bladder cancer. GSTT2B deletion may allow for reduced BCG therapy and surveillance.
Area of Science:
- Oncology
- Immunology
- Pharmacogenomics
Background:
- Glutathione-S-transferases (GSTs) are crucial for xenobiotic detoxification and influence anticancer therapy response.
- The role of specific GSTs, including GST theta 1 (GSTT1), GSTT2, and GSTT2B, in Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC) requires further elucidation.
Purpose of the Study:
- To investigate the association between GSTT1, GSTT2, and GSTT2B genetic variations and patient response to BCG treatment for NMIBC.
- To explore the functional impact of GSTT2 deletion on cellular responses to BCG in vitro and in vivo.
Main Methods:
- In vitro studies using GSTT2 knockout (KO) cell lines and dendritic cells (DCs) from GSTT2KO mice.
- Genotyping analysis of GSTT2B deletion, GSTT1, and GSTT2 promoter single-nucleotide polymorphisms in NMIBC patients (n=205) and healthy controls (n=150).
- Correlation analysis of GSTT2B genotypes with BCG treatment outcomes, including recurrence rates after varying numbers of BCG instillations.
Main Results:
- Silencing GSTT2 in MGH cells increased BCG survival and decreased reactive oxygen species.
- GSTT2B deletion (GSTT2BDel/Del) was associated with a lower recurrence rate after fewer BCG instillations compared to GSTT2B full-length (GSTT2BFL/FL) patients (12.5% vs 53.8%).
- GSTT2BFL/FL patients showed a significantly increased likelihood of recurrence post-BCG therapy (HR 5.5).
- Dendritic cells from GSTT2KO mice produced threefold more IL6 than wild-type DCs, suggesting enhanced inflammatory responses.
Conclusions:
- The GSTT2B genotype influences BCG treatment efficacy in NMIBC.
- Patients with GSTT2B deletion may benefit from reduced BCG therapy and potentially less intensive surveillance regimens.
- GSTT2B status represents a potential pharmacogenomic marker for tailoring bladder cancer immunotherapy.
