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

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posted on 17.04.2020 by Liku B Tezera, Magdalena K Bielecka, Paul Ogongo, Naomi F Walker, Matthew Ellis, Diana J Garay-Baquero, Kristian Thomas, Michaela T Reichmann, David A Johnston, Katalin Andrea Wilkinson, Mohamed Ahmed, Sanjay Jogai, Suwan N Jayasinghe, Robert J Wilkinson, Salah Mansour, Gareth J Thomas, Christian H Ottensmeier, Alasdair Leslie, Paul T Elkington
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.

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Crick (Grant ID: 10218, Grant title: Wilkinson, R FC001218)

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