PT  - JOURNAL ARTICLE
AU  - Matthew E. Griffin
AU  - Juliel Espinosa
AU  - Jessica L. Becker
AU  - Jyoti K. Jha
AU  - Gary R. Fanger
AU  - Howard C. Hang
TI  - <em>Enterococcus</em> peptidoglycan remodeling promotes immune checkpoint inhibitor therapy
AID  - 10.1101/2020.08.20.256263
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.20.256263
4099  - http://biorxiv.org/content/early/2020/08/20/2020.08.20.256263.short
4100  - http://biorxiv.org/content/early/2020/08/20/2020.08.20.256263.full
AB  - The antitumor efficacy of cancer immunotherapy has been correlated with specific species within the gut microbiota. However, molecular mechanisms by which these microbes affect host response to immunotherapy remain elusive. Here we show that specific members of the bacterial genus Enterococcus can promote anti-PD-L1 immunotherapy in mouse tumor models. The active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote antitumor activity of clinically approved checkpoint targets, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also promoted checkpoint inhibitor antitumor activity. Our data suggest that microbiota species with unique peptidoglycan remodeling activity may enhance immunotherapy and could be leveraged for next-generation adjuvants.One Sentence Summary A conserved family of secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus promote antitumor activity of immune checkpoint inhibitors.Competing Interest StatementM.E.G. and H.C.H. have filed a patent application (PCT/US2020/019038) for the commercial use of SagA-bacteria to improve checkpoint blockade immunotherapy. Rise Therapeutics (J.J. and G.R.F.) has licensed the patent to develop immunological-based biologics.