Abstract
Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB), and is also used as an immunotherapy for bladder cancer and other malignancies due to its immunostimulatory properties. Mycobacteria spp., however, are well known for their numerous immune evasion mechanisms that limit the true potential of their therapeutic use. One such major mechanism is the induction of programmed death ligand-1 (PD-L1), which mitigates adaptive immune responses. Here, we sought to unravel the molecular pathways behind PD-L1 up-regulation on antigen-presenting cells (APCs) by BCG. We found that infection of APCs with BCG induced PD-L1 up-regulation, but that this did not depend on direct infection, suggesting a soluble mediator for this effect. BCG induced potent quantities of IL-6 and IL-10, and the downstream transcription factor STAT3 was hyper-phosphorylated. Intracellular analyses revealed that levels of PD-L1 molecules were associated with the STAT3 phosphorylation state, suggesting a causal link. Neutralisation of the IL-6 or IL-10 cytokine receptors dampened STAT3 phosphorylation and BCG-mediated up-regulation of PD-L1 on APCs. Pharmacological inhibition of STAT3 achieved the same effect, confirming an autocrine-paracrine cytokine loop as a mechanism for BCG-mediated up-regulation of PD-L1. Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. These novel findings could lead to refinement of BCG as both a vaccine for infectious disease and as a cancer immunotherapy.
Highlights
Worldwide, tuberculosis (TB) is the leading cause of death due to infectious disease
Bacillus Calmette-Guérin (BCG) can induce the up-regulation of programmed death ligand-1 (PD-L1) expression on pulmonary dendritic cells (DCs) in mice[7], it is unclear whether the same holds true for macrophages
DCs and macrophages were infected with BCG over a range of multiplicities of infection (MOI) and across two time-points (24 h and 48 h); surface expression of PD-L1 was assessed by flow cytometry
Summary
Tuberculosis (TB) is the leading cause of death due to infectious disease. The mechanism of action remains to be completely elucidated, it is believed that the bacteria trigger an inflammatory response that leads to immune cell infiltration of the tumour site, facilitating immune-mediated clearance[11] This is likely to be mediated by innate (i.e. Toll-like receptor) signalling, providing scope for improvement by concomitant engagement of the adaptive immune responses, which are known to be suppressed by PD-L1. Blockade of the PD-L1 receptor in vivo during BCG immunisation led to superior CD4 T-cell responses to recall antigen, highlighting the potential utility of this pathway in clinical settings. These findings provide new targets for improving BCG as both a TB vaccine and cancer immunotherapy
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