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

Abstract

BackgroundProgrammed 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 methodsIn 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.ResultsWe 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.ConclusionThese 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.

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

“…Wang et al reported that treatment with a combination of BCG and anti-PD-L1 resulted in an enhanced anti-tumor effect in an orthotopic rat bladder cancer model by reducing tumor burden and prolonging survival. The antitumor immunity was attributed to an increase in the number and activity of tumor-infiltrating CD8+ T cells, as well as suppression of MDSCs in the TME (48).…”

Combined assessment of peritumoral Th1/Th2 polarization and peripheral immunity as a new biomarker in the prediction of BCG response in patients with high-risk NMIBC

“…17 These data suggest that the accumulation of PD-L1-expressing cells in bladder tissues could abrogate the effectiveness of BCG immunotherapy, a hypothesis reinforced by the recent finding that BCG and anti-PD-L1 combination therapy enhance the antitumor immunity in an animal model. 18 In addition to TILs, systemic immunological parameters have also been correlated with cancer outcome. The peripheral absolute lymphocyte count has been suggested to not only be a prognostic factor of survival in several tumor types 19 but also a predictor of treatment efficacy.…”

YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo‐/radio‐resistance by suppressing caspase‐mediated apoptosis

“…Thus, combinational therapy to boost immune responses by inducing cytosolic DNA with irradiation or inflammatory tumor death using a bacterial adjuvant (e.g. Bacillus Calmette–Guérin treatment) were proposed as possible strategies to improve the therapeutic efficacy of immunotherapy for UCUB . In UCUBs with YWHAZ amplification/overexpression, genes involved in interferon signaling, TLR‐4 signaling, inflammasome network, antigen presentation/TCR recognition, and CD28 co‐stimulation were found significantly downregulated (see supplementary material, Table S4).…”