Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice

Authors

• Yan Li, Sanford Burnham Prebys Medical Discovery Institute
• Roberto Tinoco, Sanford Burnham Prebys Medical Discovery Institute & University of California
• Lisa Elmén, Sanford Burnham Prebys Medical Discovery Institute
• Igor Segota, Sanford Burnham Prebys Medical Discovery Institute
• Yibo Xian, University of Nebraska- Lincoln
• Yu Fujita, Sanford Burnham Prebys Medical Discovery Institute
• Avinash Sahu, University of Maryland
• Raphy Zarecki, Tel Aviv University
• Kerrie Marie, National Institutes of Health
• Yongmei Feng, Sanford Burnham Prebys Medical Discovery Institute
• Ali Khateb, Technion Israel Institute of technology
• Dennie T. Frederick, Harvard Medical School
• Shiri K. Ashkenazi, Technion Israel Institute of technology
• Hyungsoo Kim, Sanford Burnham Prebys Medical Discovery Institute
• Eva Guijarro Perez, National Institutes of Health
• Chi-Ping Day, National Institutes of Health
• Rafael S. Segura Muñoz, University of Nebraska- LincolnFollow
• Robert Schmaltz, University of Nebraska- LincolnFollow
• Shibu Yooseph, University of Central Florida
• Miguel A. Tam, BioLegend
• Tongwu Zhang, National Cancer Institute
• Emily Avitan-Hersh, Technion Israel Institute of Technology & Technion Faculty of Medicine
• Lihi Tzur, Technion Faculty of Medicine
• Shoshana Roizman, Technion Faculty of Medicine
• Ilanit Boyango, Technion Faculty of Medicine
• Gil Bar-Sela, Technion Israel Institute of Technology & Technion Faculty of Medicine
• Amir Orian, Technion Israel Institute of technology
• Randal J. Kaufman, Sanford Burnham Prebys Medical Discovery Institute
• Marcus Bosenberg, Yale University
• Colin R. Goding, Unviversity of Oxford
• Bas Baaten, Sanford Burnham Prebys Medical Discovery Institute
• Mitchell P. Levesque, University of Zurich
• Reinhard Dummer, University of Zurich
• Kevin Brown, National Cancer Institute
• Glenn Merlino, National Institutes of Health
• Eytan Ruppin, University of Maryland & Tel Aviv University & National Institutes of Health
• Keith Flaherty, Harvard Medical School
• Amanda Ramer-Tait, University of Nebraska- LincolnFollow
• Tao Long, Sanford Burnham Prebys Medical Discovery Institute
• Scott N. Peterson, Sanford Burnham Prebys Medical Discovery Institute
• Linda M. Bradley, Sanford Burnham Prebys Medical Discovery Institute
• Ze’ev A. Ronai, Sanford Burnham Prebys Medical Discovery Institute & Technion Israel Institute of TechnologyFollow

ORCID IDs

http://orcid.org/0000-0002-8916-7303

http://orcid.org/0000-0002-8189-5939

http://orcid.org/0000-0003-4277-316X

http://orcid.org/0000-0002-1614-3909

http://orcid.org/0000-0002-8558-6711

http://orcid.org/0000-0002-3402-0478

http://orcid.org/0000-0003-0950-7548

http://orcid.org/0000-0002-7052-9546

Document Type

Article

Date of this Version

2019

Citation

NATURE COMMUNICATIONS | (2019) 10:1492 | https://doi.org/10.1038/s41467-019-09525-y | www.nature.com/naturecommunications

Comments

The Author(s) 2019

Abstract

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5−/− and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5−/− mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5−/− mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.