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

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-? is responsible for accelerated Mtb growth, and TNF-? neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-? immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-? 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-? secretion.

SUBMITTER: Tezera LB 

PROVIDER: S-EPMC7058383 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature