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

Autor: Diana J. Garay-Baquero, Christian H. Ottensmeier, M.K. Ahmed, David A. Johnston, Sanjay Jogai, Katalin A. Wilkinson, Michaela T Reichmann, Naomi F. Walker, Magdalena K. Bielecka, Liku B. Tezera, Kristian Thomas, Salah Mansour, Gareth J. Thomas, Alasdair Leslie, Suwan N. Jayasinghe, Paul T. Elkington, Matthew Ellis, Robert J. Wilkinson, Paul Ogongo
Přispěvatelé: Wellcome Trust
Rok vydání: 2020
Předmět:
CD4-Positive T-Lymphocytes
Life Sciences & Biomedicine - Other Topics
0301 basic medicine
medicine.medical_treatment
Programmed Cell Death 1 Receptor
TNF
HYPOXIA
CD8-Positive T-Lymphocytes
host-pathogen interaction
wc_302
0601 Biochemistry and Cell Biology
immunology
immune checkpoint inhibitors
Immunology and Inflammation
0302 clinical medicine
Immunopathology
INFECTION
MEDIATES RESISTANCE
Biology (General)
Granuloma
biology
General Neuroscience
General Medicine
Cell Hypoxia
Microspheres
Up-Regulation
3. Good health
tuberculosis
030220 oncology & carcinogenesis
GROWTH
Medicine
Tumor necrosis factor alpha
Immunotherapy
wf_200
MYCOBACTERIUM-TUBERCULOSIS
Life Sciences & Biomedicine
Tuberculosis
QH301-705.5
Science
HOST-DIRECTED THERAPIES
General Biochemistry
Genetics and Molecular Biology

Mycobacterium tuberculosis
03 medical and health sciences
Immune system
Latent Tuberculosis
medicine
Humans
human
Biology
Science & Technology
General Immunology and Microbiology
Tumor Necrosis Factor-alpha
business.industry
NECROSIS-FACTOR-ALPHA
medicine.disease
biology.organism_classification
Immune checkpoint
030104 developmental biology
TISSUE
inflammation
wf_140
LATENT
Cancer research
pathology
Cytokine secretion
Research Advance
MACROPHAGE
business
Zdroj: eLife, Vol 9 (2020)
ELIFE
eLife
ISSN: 2050-084X
DOI: 10.7554/elife.52668
Popis: 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.
Databáze: OpenAIRE