The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients
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
Anti–PD-1–based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients’ microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti–PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.
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Published In
Science
Volume 359 | Issue 6371
5 January 2018
5 January 2018
Copyright
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 9 July 2017
Accepted: 13 November 2017
Published in print: 5 January 2018
Acknowledgments
We thank E. Chang, A. Sivan, C. Nagler, L. Huang, P. Bleda-Ferre, N. Hubert, Z. Early, and B. Theriault for helpful discussions and M. Jarsulic, B. Choy, N. Martinec, S. Owens, S. Greenwald, H. Morrison, and J. Polinski for technical assistance. This work was supported by NIH grant R35 CA210098, a Team Science Award from the Melanoma Research Alliance, the American Cancer Society–Jules L. Plangere Jr. Family Foundation Professorship in Cancer Immunotherapy, funds from the University of Chicago Medicine Comprehensive Cancer Center, the University of Chicago Cancer Biology Training program (T32 CA009594), and The Center for Research Informatics of The University of Chicago Biological Science Division. The bioinformatics analysis was performed on Gardner High-Performance Computing clusters at Center for Research Informatics, Biological Sciences Division. Data reported in this study are tabulated in the main text and supplementary materials. The 16S and shotgun sequencing were performed at the Argonne National Laboratory and the University of Chicago-affiliated Marine Biological Laboratory, respectively; data files were deposited into The NCBI Sequence Read Archive (SRA) and are available under the accession no. SRP116709. Custom code and additional processed data used in this study are publicly available on GitHub at https://github.com/cribioinfo/sci2017_analysis. T.F.G. is an advisory board member for Roche-Genentech, Merck, Abbvie, Bayer, Aduro, and Fog Pharma. T.F.G. receives research support from Roche-Genentech, BMS, Merck, Incyte, Seattle Genetics, and Ono. T.F.G. is a shareholder/cofounder of Jounce Therapeutics. The University of Chicago holds a licensing arrangement with Evelo. T.F.G is an inventor on U.S. patent US20160354416 A1 submitted by the University of Chicago that covers the use the microbiota to improve cancer immunotherapy. J.J.L. is a consultant to and receives research funding from Bristol-Myers Squibb and Merck.
Authors
Funding Information
National Cancer Institute: T32 CA009594
Melanoma Research Alliance: CA210098
University of Chicago Medicine Comprehensive Cancer Center
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