Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α

  1. Liku B Tezera  Is a corresponding author
  2. Magdalena K Bielecka
  3. Paul Ogongo
  4. Naomi F Walker
  5. Matthew Ellis
  6. Diana J Garay-Baquero
  7. Kristian Thomas
  8. Michaela T Reichmann
  9. David A Johnston
  10. Katalin Andrea Wilkinson
  11. Mohamed Ahmed
  12. Sanjay Jogai
  13. Suwan N Jayasinghe
  14. Robert J Wilkinson
  15. Salah Mansour
  16. Gareth J Thomas
  17. Christian H Ottensmeier
  18. Alasdair Leslie
  19. Paul T Elkington
  1. University of Southampton, United Kingdom
  2. Africa Health Research Institute, South Africa
  3. Liverpool School of Tropical Medicine, United Kingdom
  4. The Francis Crick Institute, United Kingdom
  5. African Health Research Institute, South Africa
  6. University College London, United Kingdom

Abstract

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.

Data availability

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

Author details

  1. Liku B Tezera

    NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, United Kingdom
    For correspondence
    l.tezera@soton.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7898-6709
  2. Magdalena K Bielecka

    NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Paul Ogongo

    Laboratory Science, Africa Health Research Institute, Durban, South Africa
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0093-5768
  4. Naomi F Walker

    Medicine, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Matthew Ellis

    Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Diana J Garay-Baquero

    Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9450-8504
  7. Kristian Thomas

    Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Michaela T Reichmann

    Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6714-8400
  9. David A Johnston

    Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Katalin Andrea Wilkinson

    Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9796-2040
  11. Mohamed Ahmed

    African Health Research Institute, Durban, South Africa
    Competing interests
    The authors declare that no competing interests exist.
  12. Sanjay Jogai

    NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Suwan N Jayasinghe

    BioPhysics Group, UCL Institute of Biomedical Engineering, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Robert J Wilkinson

    Tuberculosis laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Salah Mansour

    NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5982-734X
  16. Gareth J Thomas

    Cancer Immunology, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3832-7335
  17. Christian H Ottensmeier

    CRUK and NIHR Experimental Cancer Medicine Center, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3619-1657
  18. Alasdair Leslie

    African Health Research Institute, Durban, South Africa
    Competing interests
    The authors declare that no competing interests exist.
  19. Paul T Elkington

    NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0390-0613

Funding

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.

Ethics

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

Reviewing Editor

  1. Bree Aldridge, Tufts University School of Medicine, United States

Publication history

  1. Received: October 17, 2019
  2. Accepted: February 19, 2020
  3. Accepted Manuscript published: February 24, 2020 (version 1)
  4. Version of Record published: March 5, 2020 (version 2)

Copyright

© 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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  1. Liku B Tezera
  2. Magdalena K Bielecka
  3. Paul Ogongo
  4. Naomi F Walker
  5. Matthew Ellis
  6. Diana J Garay-Baquero
  7. Kristian Thomas
  8. Michaela T Reichmann
  9. David A Johnston
  10. Katalin Andrea Wilkinson
  11. Mohamed Ahmed
  12. Sanjay Jogai
  13. Suwan N Jayasinghe
  14. Robert J Wilkinson
  15. Salah Mansour
  16. Gareth J Thomas
  17. Christian H Ottensmeier
  18. Alasdair Leslie
  19. Paul T Elkington
(2020)
Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α
eLife 9:e52668.
https://doi.org/10.7554/eLife.52668

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