Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α
Liku B. Tezera, Magdalena K. Bielecka, Paul Ogongo, Naomi F. Walker, Matthew J. Ellis, Diana J. Garay‐Baquero, Kristian Thomas, Michaela T. Reichmann, David A. Johnston, Katalin A. Wilkinson, Mohamed I. M. Ahmed, Sanjay Jogai, Suwan N. Jayasinghe, Robert J. Wilkinson, Salah Mansour, Gareth J. Thomas, Christian H. Ottensmeier, Alasdair Leslie, Paul Elkington
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.