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Bacillus Calmette–Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer

Authors Wang Y, Liu J, Yang X, Liu Y, Liu Y, Li Y, Sun L, Yang X, Niu H

Received 18 February 2018

Accepted for publication 12 April 2018

Published 16 May 2018 Volume 2018:11 Pages 2891—2899

DOI https://doi.org/10.2147/OTT.S165840

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 3

Editor who approved publication: Dr XuYu Yang


Yonghua Wang,1 Jing Liu,2 Xuecheng Yang,1 Yanan Liu,1 Yong Liu,1 Yanjiang Li,1 Lijiang Sun,1 Xiaokun Yang,1 Haitao Niu1

1Department of Urology, 2Department of Pediatrics, The Affiliated Hospital of Qingdao University, Qingdao 266000, People’s Republic of China

Background: Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule which promotes immunosuppression by binding to PD-1 on T-cells in tumor immunity. We have previously identified that activation of toll like receptor 4 (TLR-4), which serves an important role in the induction of antitumor immune response during Bacillus Calmette–Guérin (BCG) immunotherapy, could upregulate PD-L1 expression in bladder cancer (BCa) cells through the classical mitogen-activated protein kinase (MAPK) pathway and subsequently weaken the cytotoxicity of cytotoxic T lymphocyte (CTL). It is, therefore, necessary to investigate the possible potential relationship between PD-L1 expression and BCG immunotherapy.
Materials and methods: In this study we investigated the effects of BCG treatment on PD-L1 expression in BCa cells and also evaluated the efficacy of BCG and anti-PD-L1 combination therapy in immunocompetent orthotopic rat BCa models.
Results: We found that PD-L1 expression was obviously upregulated in BCa cells in response to BCG treatment both in vitro and in vivo. Moreover, BCG and anti-PD-L1 combination treatment activated a potent antitumor immune response with the increase in the number and activity of tumor-infiltrating CD8+ T cells, as well as the reduction in myeloid-derived suppressor cells (MDSCs), and eventually elicits prominent tumor growth inhibition and prolonged survival, and was found to be much more effective than either agent alone.
Conclusion: These findings highlight the adaptive dynamic regulation of PD-L1 in response to BCG immunotherapy and suggest that combination of BCG immunotherapy with PD-L1 blockade may be an effective antitumor strategy for improving treatment outcomes of BCa.

Keywords: BCG, PD-L1, bladder cancer, immunotherapy, combination therapy
 

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