Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors
Good bacteria help fight cancer
Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila. Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer.
Abstract
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12–dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.
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Volume 359 | Issue 6371
5 January 2018
5 January 2018
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Received: 5 April 2017
Accepted: 20 September 2017
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Acknowledgments
We thank the animal facility team and V. Rouffiac from the imaging platform of Gustave Roussy, as well as S. Jabs for technical help. The data reported in this manuscript are tabulated in the main paper and the supplementary materials. The metagenomic shotgun sequencing data are available from the European Nucleotide Archive (EMBL-EBI) under accession number PRJEB22863. B.R. was supported by Gustave Roussy Course of Excellence in Oncology–Fondation Philanthropia and a McGill University Townsend hematology research fellowship award. L.Z. and G.K. were supported by the Ligue contre le Cancer (équipe labelisée), Agence Nationale de la Recherche (ANR)–Projets blancs, ANR under the frame of E-Rare-2 (ERA-Net for Research on Rare Diseases), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Institut Universitaire de France, Fondation pour la Recherche Médicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LeDucq Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), the Paris Alliance of Cancer Research Institutes (PACRI), and philanthropia (E. Badinter and N. Meyer). L.Z., E.L.C., and B.R. are inventors on patent EP17305206 and European license 16306779.6 held by Institut Gustave Roussy that covers use of microbial modulators for PD1/PD-L1/PD-L2 mAb-based treatments. L.Z. and G.K. are cofounders of EverImmune, a biotech company focused on the use of commensal bacteria for cancer treatment.
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RE: Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumours
To the Editor,
I read with keen interest the article authored by Routy B. et al (1) and entitled: "Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumours."
This series of experiments sought to improve understanding of the gut microbial imbalance and maladaptation associated with (1) cancer and (2) concomitant antibiotic use, and explore the potential impact of this dysbiosis on resistance to immune checkpoint inhibition with the PD-1 blockade when used in cancer patients, and mice with established tumours.
The authors demonstrated that the efficacy of PD-1 blockade in cancer patients and in tumour bearing mice, was reduced in the presence of concomitant antibiotic administration. The bacteria most significantly associated with responders (R) in RCC and NSCLC was A. municiphilia. Importantly, A. municiphilia was also found to be overrepresented in the stool samples of cancer patients at the time of their diagnosis and it was these particular patients that were shown to benefit from PD-1 checkpoint inhibition.
Experiments involving fecal microbiota transplantation (FMT) derived from cancer patient stool samples and administered to (1) Germ free animals and (2) antibiotic treated mice in SPF conditions, showed that stool samples from clinical responders to treatment (R) conferred sensitivity to PD-1 blockade, while clinical non-responders (NR) produced resistance. Further work supported the overall findings that the state of intestinal microbiota was able to affect checkpoint inhibition and influence outcomes in mouse models.
Monocolonization with A.municiphilia or bicolonization with A. municiphilia combined with E.hirae restored PD-1 inhibition efficacy in germ free and antibiotic treated SPF mice who had received prior FMT from NR patients. In addition, the role of CCR9+CXCR3+CD4+ T cells and accumulation in murine tumours after recolonization with oral administration of A.municiphilia and subsequent FMT from NR cancer patients, was a significant point of interest regarding the resultant immunological impact.
Overall NRs showed an imbalance in their gut flora composition, that correlated with impaired immune cell activity thus resident gut bacteria were shown to affect patient responses to cancer immunotherapy. This highlighted the role of maintaining healthy gut flora to support patients combating cancer. An area of natural focus includes the role of diet and other factors in supporting healthy gut flora and further understanding of the influences on immune responses within this context.
Overall an exciting series of results highlighting the connection between the gut microbiome and PD-1 blockade outcomes in cancer bearing mice and humans.
Respectfully yours,
Dr Dianne Sika-Paotonu C.Q.S.
Associate Dean (Pacific)
Senior Lecturer, Pathology & Molecular Medicine
Wellington School of Medicine and Health Sciences, University of Otago, New Zealand
Honorary Research Associate, Telethon Kids Institute, Australia
Honorary Research Associate, Victoria University of Wellington, New Zealand
Affiliate Investigator Maurice Wilkins Centre for Molecular Biodiscovery
University of Auckland, New Zealand
References:
1. Routy B, Le Chatelier E, Derosa L, Duong CP, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-7.