Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy

Abstract

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 Enterococcus 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 E. faecalis 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.

Chemoproteomics of microbiota metabolites reveals small-molecule agonists for orphan receptor GPRC5A

“…For example, two common Firmicutes, Ruminococcus gnavus and Clostridium sporogenes converts Trp to TA through reductive metabolism by the Trp decarboxylase (TrpDC). 44 Alternatively, PEA is known as a product of bacterial species including Enterococcus faecalis 45 and Morganella morganii 9 , whereas tyramine has been identified in the growth media of different Enterococcus and Lactobacillus species. 45,46 To identify microbiota species that can activate GPRC5A, we examined the growth media of different bacterial species and strains predicted to metabolize aAAs into their corresponding monoamines.…”

“…The analysis of TyrDC orthologs across different species in the human microbiome was conducted as previously described. 9 Briefly, GenBank coding sequences from genome FASTA assemblies within the Human Microbiome Project 47 were downloaded via BioProject Accession number PRJNA28331 and queried by BLASTP using TyrDC E. faecium Com15 (AZV35689.1). For genomes with multiple hits, the hit sequence with the highest percent identity with the query sequence was chosen as the TyrDC ortholog.…”

“…1–3 For example, microbe-associated molecular patterns (MAMPs) such as lipopolysaccharides (LPS) can engage toll-like receptors (TLRs) to maintain intestinal epithelial homeostasis 4 and modulate infant autoimmunity 5 . In addition, microbiota-derived cyclic dinucleotides 6 and peptidoglycan fragments 7,8 initiate host immune response and enhance the efficacy of immune checkpoint inhibitor for cancer therapy 9,10 . Beyond generating MAMPs that engage canonical pattern recognition receptors (PRRs), microbiota metabolism of dietary components (e.g., polysaccharides, amino acids and lipids) 11 , host metabolites (e.g.…”

Human Microbiome and Its Medical Applications

“…The combination of three engineered bacteria strains effectively reduced tumor volume and increased survival. In addition to direct enrichment to tumor sites, engineered microbes can also remotely express relevant antigens or immunomodulatory substances, thereby enhancing tumor therapeutic effects ( Chung et al, 2021 ; Griffin et al, 2021 ). In summary, an engineered microbe as a live platform to enhance immune response and tumor killers will become an important tool in cancer treatment.…”

Comparative Analysis of Predictive Biomarkers for PD-1/PD-L1 Inhibitors in Cancers: Developments and Challenges

“…Other bacteria, including Bacteroides stercoris , Parabacteroides distasonis , and Fournierella massiliensis were found to be enriched in responders compared with non-responders of a combined immune checkpoint blockade targeting both CTLA-4 and PD-1 [ 130 ]. One study recently observed that bacteria expressing SagA improve the efficacy of checkpoint inhibitor therapy in animal models [ 186 ]. In addition, a fecal microbiota transplant has been proven to promote the response to anti–PD-1 therapy by reprogramming the tumor microenvironment in immunotherapy-refractory melanoma patients [ 187 , 188 ].…”