Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Response to Bacillus Calmette–Guérin Immunotherapy in Bladder Cancer Patients

Author:

Rahmat Juwita N.1ORCID,Tham Sin Mun1ORCID,Ong Ting Li2ORCID,Lim Yew Koon1ORCID,Patwardhan Mugdha Vijay1ORCID,Nee Mani Lata Raman1,Kamaraj Revathi1ORCID,Chan Yiong Huak3ORCID,Chong Tsung Wen45ORCID,Chiong Edmund16,Esuvaranathan Kesavan16ORCID,Mahendran Ratha1ORCID

Affiliation:

1. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore

2. School of Engineering, Biomedical Engineering, Temasek Polytechnic, Singapore 529757, Singapore

3. Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

4. Department of Urology, Singapore General Hospital, Singapore 169608, Singapore

5. Division of Surgery & Surgical Oncology, National Cancer Center Singapore, Singapore 168583, Singapore

6. Department of Urology, National University Hospital, National University Health System, Singapore 119074, 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.

Funder

National University Health System

Joseph Lim Boon Tiong Urology Cancer Research Initiative

Publisher

MDPI AG

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