Abstract |
The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.
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Authors | Melanie R Rutkowski, Tom L Stephen, Nikolaos Svoronos, Michael J Allegrezza, Amelia J Tesone, Alfredo Perales-Puchalt, Eva Brencicova, Ximena Escovar-Fadul, Jenny M Nguyen, Mark G Cadungog, Rugang Zhang, Mariana Salatino, Julia Tchou, Gabriel A Rabinovich, Jose R Conejo-Garcia |
Journal | Cancer cell
(Cancer Cell)
Vol. 27
Issue 1
Pg. 27-40
(Jan 12 2015)
ISSN: 1878-3686 [Electronic] United States |
PMID | 25533336
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- Galectin 1
- Interleukin-17
- Interleukin-6
- Toll-Like Receptor 5
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Topics |
- Animals
- Cell Line, Tumor
- Cells, Cultured
- Galectin 1
(metabolism)
- Gene Expression Regulation, Neoplastic
- Humans
- Interleukin-17
(metabolism)
- Interleukin-6
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Microbiota
- Molecular Sequence Data
- Neoplasm Transplantation
- Neoplasms
(immunology, pathology)
- Polymorphism, Single Nucleotide
- Signal Transduction
- Toll-Like Receptor 5
(genetics, metabolism)
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