Abstract
Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
Copyright © 2015, American Association for the Advancement of Science.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Animals
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Anti-Bacterial Agents / pharmacology
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Antibodies, Monoclonal / adverse effects
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Antibodies, Monoclonal / therapeutic use*
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Bacteroides / immunology*
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CTLA-4 Antigen / antagonists & inhibitors*
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CTLA-4 Antigen / immunology
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Dysbiosis / immunology
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Fecal Microbiota Transplantation
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Female
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Gastrointestinal Microbiome / drug effects
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Gastrointestinal Microbiome / immunology*
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Germ-Free Life / immunology
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Humans
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Immunologic Memory
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Immunotherapy
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Intestines / immunology
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Intestines / microbiology
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Ipilimumab
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Male
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Melanoma / therapy*
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Mice
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Mice, Inbred C57BL
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Middle Aged
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Skin Neoplasms / therapy*
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T-Lymphocytes / immunology
Substances
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Anti-Bacterial Agents
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Antibodies, Monoclonal
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CTLA-4 Antigen
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Ipilimumab
Associated data
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BioProject/IDPRJNA299112
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SRA/SRP065109
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SRA/SRR2758006
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SRA/SRR2758031
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SRA/SRR2758178
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SRA/SRR2758179
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SRA/SRR2758180
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SRA/SRR2758181
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SRA/SRR2768454
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SRA/SRR2768457