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Cancer Cell. 2015 Jan 12;27(1):27-40. doi: 10.1016/j.ccell.2014.11.009. Epub 2014 Dec 18.

Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.

Author information

1
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
2
Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
3
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
4
Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
5
Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA; Rena Rowan Breast Center, University of Pennsylvania, Philadelphia, PA 19104-1693, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
6
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.
7
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.

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.

PMID:
25533336
PMCID:
PMC4293269
DOI:
10.1016/j.ccell.2014.11.009
[Indexed for MEDLINE]
Free PMC Article

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