Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α
Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al, 2017). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-α is responsible for accelerated Mtb growth, and TNF-α neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-α immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-α concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-α secretion.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for for all figures as a data resource file
Article and author information
Medical Research Council (MR/P023754/1)
- Paul T Elkington
Medical Research Council (MR/N006631/1)
- Paul T Elkington
Wessex Medical Research (Innovation Grant 2017)
- Liku B Tezera
Wellcome Trust (210662/Z/18/Z)
- Alasdair Leslie
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: All ethical approvals were in place from the appropriate regulatory organisations in both the UK and South Africa, as cited in the methods
- Bree Aldridge, Tufts University School of Medicine, United States
- Received: October 17, 2019
- Accepted: February 19, 2020
- Accepted Manuscript published: February 24, 2020 (version 1)
- Version of Record published: March 5, 2020 (version 2)
© 2020, Tezera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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