Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor immunotherapy

The antitumor efficacy of cancer immunotherapy can correlate with the presence of certain bacterial species within the gut microbiome, and yet many of the molecular mechanisms that impact host response to immunotherapy remain elusive. Here, we show that members of the bacterial genus Enterococcus modulate response to 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 non-protective E. faecalis was sufficient to promote anti-PD-L1 response, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also augmented anti-PD-L1 efficacy. Together, our data suggest that microbiota species with unique peptidoglycan remodeling activity and muropeptide-based therapeutics may enhance cancer immunotherapy and could be leveraged as next-generation adjuvants.

肿瘤免疫治疗的抗肿瘤疗效可与肠道微生物组内特定细菌物种的存在相关联，但目前诸多影响宿主对免疫治疗应答的分子机制仍尚不明确。本研究表明，肠球菌属（Enterococcus）的细菌成员可在小鼠肿瘤模型中调控宿主对免疫检查点抑制剂类免疫治疗的应答。具有活性的肠球菌可表达并分泌NlpC/p60肽聚糖水解酶SagA的同源蛋白，该酶可产生免疫活性肽聚糖肽（muropeptides）。在无保护作用的粪肠球菌（E. faecalis）中表达SagA即可有效促进抗PD-L1治疗应答，且该活性依赖于肽聚糖感受器Nod2。值得注意的是，经SagA改造的益生菌或合成肽聚糖肽同样可增强抗PD-L1治疗的疗效。综上，本研究数据表明，具备独特肽聚糖重塑活性的菌群物种以及基于肽聚糖肽的治疗手段可增强肿瘤免疫治疗效果，有望作为新一代佐剂加以开发利用。