PLoS pathogens, 2019-02, Vol.15 (2), p.e1007583-e1007583
2019
Details
- Autor(en) / Beteiligte
- Titel
- TLR4 signaling improves PD-1 blockade therapy during chronic viral infection
- Ist Teil von
- PLoS pathogens, 2019-02, Vol.15 (2), p.e1007583-e1007583
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- CD8 T cells are necessary for the elimination of intracellular pathogens, but during chronic viral infections, CD8 T cells become exhausted and unable to control the persistent infection. Programmed cell death-1 (PD-1) blockade therapies have been shown to improve CD8 T cell responses during chronic viral infections. These therapies have been licensed to treat cancers in humans, but they have not yet been licensed to treat chronic viral infections because limited benefit is seen in pre-clinical animal models of chronic infection. In the present study, we investigated whether TLR4 triggering could improve PD-1 therapy during a chronic viral infection. Using the model of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we show that TLR4 triggering with sublethal doses of lipopolysaccharide (LPS) followed by PD-1 blockade results in superior improvement in circulating virus-specific CD8 T cell responses, relative to PD-1 blockade alone. Moreover, we show that the synergy between LPS and PD-1 blockade is dependent on B7 costimulation and mediated by a dendritic cell (DC) intrinsic mechanism. Systemic LPS administration may have safety concerns, motivating us to devise a safer regimen. We show that ex vivo activation of DCs with LPS, followed by adoptive DC transfer, results in a similar potentiation of PD-1 therapy without inducing wasting disease. In summary, our data demonstrate a previously unidentified role for LPS/TLR4 signaling in modulating the host response to PD-1 therapy. These findings may be important for developing novel checkpoint therapies against chronic viral infection.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7374, 1553-7366eISSN: 1553-7374DOI: 10.1371/journal.ppat.1007583Titel-ID: cdi_plos_journals_2251133263
- Format
- –
- Schlagworte
- Adoptive Transfer, Animal models, Animals, Antigens, Apoptosis, B7 antigen, Biochemistry, Biology and life sciences, Cancer, Care and treatment, CD8 antigen, CD8-Positive T-Lymphocytes - physiology, Cell activation, Cell death, Cellular signal transduction, Chronic Disease, Chronic infection, Cytotoxicity, Dendritic Cells, Experiments, Female, Genomes, HIV, Human immunodeficiency virus, Immunology, Immunotherapy, Infection, Infection control, Infections, Lipopolysaccharides, Lipopolysaccharides - pharmacology, Lymphocyte Activation, Lymphocytes, Lymphocytes T, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus - immunology, Lymphocytic choriomeningitis virus - pathogenicity, Male, Medical research, Medicine, Medicine and health sciences, Mice, Mice, Inbred C57BL, Mitogens, Novels, Pathogenic microorganisms, PD-1 protein, Potentiation, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - immunology, Signal Transduction, Signaling, T cells, Therapy, TLR4, TLR4 protein, Toll-Like Receptor 4 - immunology, Toll-Like Receptor 4 - metabolism, Toll-like receptors, Viral infections, Viral meningitis, Virus Diseases - immunology, Viruses