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

被引：251

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

来源：

CANCER CELL | 2015年 / 27卷 / 01期

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

页码：27 / 40

页数：14

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