Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée Ligue Nationale contre le Cancer, Villejuif, France.
Cell Death Differ. 2021 Jul;28(7):2276-2295. doi: 10.1038/s41418-021-00753-8. Epub 2021 May 11.
A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
肠道微生物组的偏差谱预测了对癌症免疫疗法的耐药性。肠球菌 hirae 补偿了各种肿瘤模型中的癌症相关的菌群失调。然而，E. hirae 恢复与抗生素同时使用的环磷酰胺疗效的机制仍未明确。在这里，我们分析了这种抗癌益生菌的多方面作用模式。首先，E. hirae 引发了胸腺细胞的迁移，并触发了全身性和肿瘤内 IFNγ 产生和 CD137 表达的效应记忆 T 细胞反应。其次，E. hirae 在肠细胞中激活了自噬机制，并介导了 ATG4B 依赖性的抗癌作用，这可能是由于其增加局部多胺传递的能力所致。第三，E. hirae 使宿主微生物组向富含双歧杆菌的生态系统转移。与活菌相比，其巴氏杀菌细胞或膜泡缺乏抗癌特性。这些多效性功能允许设计最佳的免疫疗法，将 E. hirae 与 CD137 激动性抗体、亚精胺或动物双歧杆菌结合使用。我们推测，活菌的免疫、代谢、上皮和微生物作用模式协同作用，以规避对治疗的原发性耐药。
