Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy

The antitumor efficacy of cancer immunotherapy can correlate with the presence of certain bacterial species within the gut microbiome. However, many of the molecular mechanisms that influence host response to immunotherapy remain elusive. In this study, we show that members of the bacterial genus im...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2021-08, Vol.373 (6558), p.1040-1046
Main Authors: Griffin, Matthew E, Espinosa, Juliel, Becker, Jessica L, Luo, Ji-Dung, Carroll, Thomas S, Jha, Jyoti K, Fanger, Gary R, Hang, Howard C
Format: Article
Language:English
Subjects:
Adjuvants
Animal models
Animals
Anticancer properties
Antitumor activity
B7-H1 Antigen - antagonists & inhibitors
Bacteria
Bacterial Load
Bacterial Proteins - metabolism
Cancer
Cancer immunotherapy
Cell walls
Enterococcus
Enterococcus - enzymology
Enterococcus - metabolism
Enterococcus faecalis - metabolism
Enterococcus faecium - metabolism
Feedback (Response)
Gastrointestinal Microbiome
Hydrolase
Immune checkpoint
Immune Checkpoint Inhibitors - therapeutic use
Immunotherapy
Inhibitors
Intestinal microflora
Melanoma, Experimental - immunology
Melanoma, Experimental - therapy
Mice
Mice, Inbred C57BL
Microbiomes
Microbiota
Molecular modelling
N-Acetylmuramoyl-L-alanine Amidase - metabolism
NOD2 protein
Nod2 Signaling Adaptor Protein - metabolism
Outcomes of Treatment
PD-L1 protein
Peptide Fragments - metabolism
Peptidoglycan - metabolism
Peptidoglycan hydrolase
Probiotics
Signal Transduction
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Description
Summary:The antitumor efficacy of cancer immunotherapy can correlate with the presence of certain bacterial species within the gut microbiome. However, many of the molecular mechanisms that influence host response to immunotherapy remain elusive. In this study, we show that members of the bacterial genus improve checkpoint inhibitor immunotherapy in mouse tumor models. Active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in nonprotective was sufficient to promote immunotherapy response, and its activity required the peptidoglycan sensor NOD2. Notably, SagA-engineered probiotics or synthetic muropeptides also augmented anti-PD-L1 antitumor efficacy. Taken together, our data suggest that microbiota species with specialized peptidoglycan remodeling activity and muropeptide-based therapeutics may enhance cancer immunotherapy and could be leveraged as next-generation adjuvants.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abc9113