Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation

被引:250
作者
Rutkowski, Melanie R. [1 ]
Stephen, Tom L. [1 ]
Svoronos, Nikolaos [1 ]
Allegrezza, Michael J. [1 ]
Tesone, Amelia J. [1 ]
Perales-Puchalt, Alfredo [1 ]
Brencicova, Eva [1 ]
Escovar-Fadul, Ximena [1 ]
Nguyen, Jenny M. [1 ]
Cadungog, Mark G. [2 ]
Zhang, Rugang [3 ]
Salatino, Mariana [4 ]
Tchou, Julia [4 ,5 ,6 ]
Rabinovich, Gabriel A. [7 ]
Conejo-Garcia, Jose R. [1 ]
机构
[1] Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, Philadelphia, PA 19104 USA
[2] Christiana Care Hlth Syst, Helen F Graham Canc Ctr, Newark, DE 19713 USA
[3] Wistar Inst Anat & Biol, Gene Express & Regulat Program, Philadelphia, PA 19104 USA
[4] Univ Penn, Dept Surg, Div Endocrine & Oncol Surg, Philadelphia, PA 19104 USA
[5] Univ Penn, Rena Rowan Breast Ctr, Philadelphia, PA 19104 USA
[6] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA
[7] Inst Biol & Med Expt IBYME CONICET, Lab Inmunopatol, Buenos Aires, DF, Argentina
关键词
RECEPTOR POLYMORPHISMS; SUSCEPTIBILITY; CELLS; FLAGELLIN;
D O I
10.1016/j.ccell.2014.11.009
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 gamma delta 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.
引用
收藏
页码:27 / 40
页数:14
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