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

Tezera, Liku B, Bielecka, Magdalena K, Ogongo, Paul, Walker, Naomi ORCID: https://orcid.org/0000-0002-3345-7694, Ellis, Matthew, Garay-Baquero, Diana J, Thomas, Kristian, Reichmann, Michaela 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, Vol 9, Issue e52668, e52668.

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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.

Item Type:	Article
Subjects:	WC Communicable Diseases > Infection. Bacterial Infections > Other Bacterial Infections. Zoonotic Bacterial Infections > WC 302 Actinomycetales infections. Mycobacterium infections WF Respiratory System > WF 140 Diseases of the respiratory system (General) WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.7554/eLife.52668
Depositing User:	Stacy Murtagh
Date Deposited:	25 Feb 2020 14:56
Last Modified:	25 Feb 2020 14:56
URI:	https://archive.lstmed.ac.uk/id/eprint/13830

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