Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α.
Liku B TezeraMagdalena K BieleckaPaul OgongoNaomi F WalkerMatthew EllisDiana J Garay-BaqueroKristian ThomasMichaela T ReichmannDavid A JohnstonKatalin Andrea WilkinsonMohamed AhmedSanjay JogaiSuwan N JayasingheRobert J WilkinsonSalah MansourGareth J ThomasChristian Hermann OttensmeierAlasdair LesliePaul T ElkingtonPublished in: eLife (2020)
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.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- rheumatoid arthritis
- endothelial cells
- immune response
- ejection fraction
- newly diagnosed
- squamous cell carcinoma
- pulmonary hypertension
- poor prognosis
- weight gain
- emergency department
- cystic fibrosis
- chronic kidney disease
- prognostic factors
- long non coding rna
- toll like receptor
- hiv aids
- pluripotent stem cells
- hepatitis c virus
- young adults
- inflammatory response
- patient reported outcomes
- replacement therapy