Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-$α$. Tezera, L. B, Bielecka, M. K, Ogongo, P., Walker, N. F, Ellis, M., Garay-Baquero, D. J, Thomas, K., Reichmann, M. T, Johnston, D. A, Wilkinson, K. A, Ahmed, M., Jogai, S., Jayasinghe, S. N, Wilkinson, R. J, Mansour, S., Thomas, G. J, Ottensmeier, C. H, Leslie, A., & Elkington, P. T eLife, 9:e52668, feb, 2020. ![Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-$α$ [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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.
@article{Tezera2020a,
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-$\alpha$ is responsible for accelerated Mtb growth, and TNF-$\alpha$ neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-$\alpha$ immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-$\alpha$ 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-$\alpha$ secretion.},
author = {Tezera, Liku B and Bielecka, Magdalena K and Ogongo, Paul and Walker, Naomi F and Ellis, Matthew and Garay-Baquero, Diana J and Thomas, Kristian and Reichmann, Michaela T and Johnston, David A and Wilkinson, Katalin A and Ahmed, Mohamed and Jogai, Sanjay and Jayasinghe, Suwan N and Wilkinson, Robert J and Mansour, Salah and Thomas, Gareth J and Ottensmeier, Christian H and Leslie, Alasdair and Elkington, Paul T},
doi = {10.7554/eLife.52668},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tezera et al. - 2020 - Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-$\alpha$.pdf:pdf},
issn = {2050-084X},
journal = {eLife},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
pages = {e52668},
title = {{Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-$\alpha$}},
url = {https://elifesciences.org/articles/52668},
volume = {9},
year = {2020}
}
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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. 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