Abstract
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.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank the animal facility team and V. Rouffiac from the imaging platform of Gustave Roussy.
Funding
A-GG was supported by Fondation pour la Recherche Médicale (FRM). LZ and GK were supported by the Ligue contre le Cancer (équipes labellisées); Agence National de la Recherche (ANR)—Projets blancs; CANTO study (ANR-10-COHO-0004); ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), FRM; a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière (ANR-16-RHUS-0008); the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).
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LZ, RD, and AGG conceived the study, analyzed the data, provided the intellectual guidance, and wrote the paper with the help of GK. AGG, RD, AF, RW, BQ, FL, KI, LM, MTA, EP, LD, SD, FAp, NB, MM-N, DD, GC, SY, OK, ML, and AJ performed the experiments and analyzed the data. LD and FAn provided patients’ feces. ELC, NP, NS, and VL analyzed the bioinformatics data. DR and IGB provided the mice, bacteria, and reagents. IGB and GK also provided intellectual guidance.
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RD, LZ, and GK are cofounders of EverImmune, a biotech company focused on the use of commensal bacteria for cancer treatment. FL and RD were employees of EverImmune.
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The institutional board of animal ethics and Ministère de la Recherche approved all mouse experimental settings (permission numbers: 2014-074-501, 2016-109-7450, 2018-013-13366, and 2019-076-23184). Stools from breast cancer patients were collected from CANTO study (NCT01993498). The study was approved by the Comité de Protection des Personnes IDF7 (Bicêtre, project: 11-039). All patients gave their consent for the use of their fecal material and the related data, to be published.
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Goubet, AG., Wheeler, R., Fluckiger, A. et al. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae. Cell Death Differ 28, 2276–2295 (2021). https://doi.org/10.1038/s41418-021-00753-8
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DOI: https://doi.org/10.1038/s41418-021-00753-8
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