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

Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α
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., 2017a). 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 is 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-a is responsible for accelerated Mtb growth, and TNF-a neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-a immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-a 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-a secretion.

2050-084X
Tezera, Liku Bekele
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Bielecka, Magdalena K.
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Ogongo, Paul
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Walker, Naomi F.
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Ellis, Matthew
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Garay-Baquero, Diana
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Thomas, Kristian
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Reichmann, Michela T.
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Johnston, David A.
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Wilkinson, Katalin Andrea
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Ahmed, Mohamed
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Jogai, Sanjay
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Jayasinghe, Suwan N.
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Wilkinson, Robert J.
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Mansour, Salah
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Thomas, Gareth J.
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Ottensmeier, Christian H.
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Leslie, Alasdair
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Elkington, Paul T.
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Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Bielecka, Magdalena K.
90391ea3-aa1f-4104-a893-568c138718a2
Ogongo, Paul
695adbcd-0e29-48e0-b6a2-4a42fad39175
Walker, Naomi F.
e586ffdf-ae4b-46fa-83a1-db72501d17c1
Ellis, Matthew
bdf723b8-cd9c-4c90-9296-38c5f2877e16
Garay-Baquero, Diana
da9136fe-3d47-4d04-8ab3-96bfe17a773c
Thomas, Kristian
e9b90898-c510-43a0-af9a-4ddf24345e80
Reichmann, Michela T.
a2c90ce6-ed4a-43e1-827e-f7ddde682a47
Johnston, David A.
a2e714e5-5f06-446d-8159-a1ec8d70fcd6
Wilkinson, Katalin Andrea
dead17f9-7f31-4a4f-8fbf-4610ccf96885
Ahmed, Mohamed
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Jogai, Sanjay
18c2f36b-4572-46d5-b17d-a6d2cdaa916c
Jayasinghe, Suwan N.
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Wilkinson, Robert J.
6968bb11-0079-45f4-85e3-e0cd45ef82b1
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Thomas, Gareth J.
e9d17d4c-225c-4840-b95c-777ca4b1638c
Ottensmeier, Christian H.
42b8a398-baac-4843-a3d6-056225675797
Leslie, Alasdair
84d4f578-f3c0-46cc-9c83-a8d9bb40c38c
Elkington, Paul T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15

Tezera, Liku Bekele, Bielecka, Magdalena K., Ogongo, Paul, Walker, Naomi F., Ellis, Matthew, Garay-Baquero, Diana, Thomas, Kristian, Reichmann, Michela T., Johnston, David A., Wilkinson, Katalin Andrea, Ahmed, Mohamed, Jogai, Sanjay, Jayasinghe, Suwan N., Wilkinson, Robert J., Mansour, Salah, Thomas, Gareth J., Ottensmeier, Christian H., Leslie, Alasdair and Elkington, Paul T. (2020) Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α. eLife, 9, [e52668]. (doi:10.7554/eLife.52668).

Record type: Article

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., 2017a). 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 is 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-a is responsible for accelerated Mtb growth, and TNF-a neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-a immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-a 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-a secretion.

Text
Tezera_eLife_author_accepted_200220_comp - Accepted Manuscript
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More information

Accepted/In Press date: 19 February 2020
e-pub ahead of print date: 5 March 2020
Published date: 3 May 2020

Identifiers

Local EPrints ID: 438296
URI: http://eprints.soton.ac.uk/id/eprint/438296
ISSN: 2050-084X
PURE UUID: 2da789b6-89a8-4a73-870a-29cb0480e360
ORCID for Liku Bekele Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Diana Garay-Baquero: ORCID iD orcid.org/0000-0002-9450-8504
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X
ORCID for Paul T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

Catalogue record

Date deposited: 04 Mar 2020 17:33
Last modified: 26 Nov 2021 03:18

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Contributors

Author: Magdalena K. Bielecka
Author: Paul Ogongo
Author: Naomi F. Walker
Author: Matthew Ellis
Author: Diana Garay-Baquero ORCID iD
Author: Kristian Thomas
Author: Michela T. Reichmann
Author: David A. Johnston
Author: Katalin Andrea Wilkinson
Author: Mohamed Ahmed
Author: Sanjay Jogai
Author: Suwan N. Jayasinghe
Author: Robert J. Wilkinson
Author: Salah Mansour ORCID iD
Author: Gareth J. Thomas
Author: Alasdair Leslie

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