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



Tezera, Liku B, Bielecka, Magdalena K, Ogongo, Paul, Walker, Naomi F, Ellis, Matthew, Garay-Baquero, Diana J, Thomas, Kristian, Reichmann, Michaels T, Johnston, David A, Wilkinson, Katalin Andrea
et al (show 9 more authors) (2020) Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-alpha. ELIFE, 9. 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., 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-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
Uncontrolled Keywords: CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Humans, Mycobacterium tuberculosis, Granuloma, Tumor Necrosis Factor-alpha, Immunotherapy, Microspheres, Cell Hypoxia, Up-Regulation, Latent Tuberculosis, Programmed Cell Death 1 Receptor
Depositing User: Symplectic Admin
Date Deposited: 18 May 2020 09:25
Last Modified: 18 Jan 2023 23:51
DOI: 10.7554/eLife.52668
Open Access URL: http://doi.org/10.7554/eLife.52668
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3087747