Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer.
Animals
BCG Vaccine
/ immunology
CD8-Positive T-Lymphocytes
/ immunology
Cancer Vaccines
/ immunology
Cell Line, Tumor
Cytokines
/ biosynthesis
Dinucleoside Phosphates
/ biosynthesis
Humans
Immunity, Innate
/ immunology
Macrophages
/ immunology
Membrane Proteins
/ metabolism
Mice
Myeloid Cells
/ immunology
Pathogen-Associated Molecular Pattern Molecules
/ immunology
Rats
Urinary Bladder Neoplasms
/ immunology
Urothelium
/ pathology
Vaccination
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 02 2022
15 02 2022
Historique:
received:
18
11
2020
accepted:
27
01
2022
entrez:
16
2
2022
pubmed:
17
2
2022
medline:
3
3
2022
Statut:
epublish
Résumé
In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING). We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher pro-inflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhances epigenetic and metabolomic changes. In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality. These results indicate that trained immunity levels and antitumor efficacy may be increased by modifying BCG to express higher levels of key PAMP molecules.
Identifiants
pubmed: 35169141
doi: 10.1038/s41467-022-28509-z
pii: 10.1038/s41467-022-28509-z
pmc: PMC8847416
doi:
Substances chimiques
BCG Vaccine
0
Cancer Vaccines
0
Cytokines
0
Dinucleoside Phosphates
0
Membrane Proteins
0
Pathogen-Associated Molecular Pattern Molecules
0
STING1 protein, human
0
cyclic diadenosine phosphate
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
878Subventions
Organisme : NIAID NIH HHS
ID : R01 AI037856
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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