MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION
The dominant TLR5 R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extra-mucosal locations by increasing systemic IL-6, which drives mobilization of myeloid derived suppressor cells (MDSCs). Mechanis...
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| Published in | Cancer cell Vol. 27; no. 1; pp. 27 - 40 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
18.12.2014
|
| Online Access | Get full text |
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| Abstract | The dominant
TLR5
R392X
polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extra-mucosal 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 anti-tumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently up-regulated 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, anti-tumor immunity and the clinical outcome of cancer patients are influenced by a common
TLR5
polymorphism. |
|---|---|
| AbstractList | The dominant
TLR5
R392X
polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extra-mucosal 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 anti-tumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently up-regulated 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, anti-tumor immunity and the clinical outcome of cancer patients are influenced by a common
TLR5
polymorphism. |
| Author | Brencicova, Eva Perales-Puchalt, Alfredo Cadungog, Mark G. Allegrezza, Michael J. Salatino, Mariana Escovar-Fadul, Ximena Nguyen, Jenny M. Rabinovich, Gabriel A. Zhang, Rugang Conejo-Garcia, Jose R. Rutkowski, Melanie R. Svoronos, Nikolaos Tesone, Amelia J. Tchou, Julia Stephen, Tom L. |
| AuthorAffiliation | 2 Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA 7 Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina 1 Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA 3 Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA 5 Rena Rowan Breast Center, University of Pennsylvania, Philadelphia, PA 19104-1693, USA 6 Abramson Cancer Center Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-1693, USA 4 Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA |
| AuthorAffiliation_xml | – name: 1 Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA – name: 2 Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA – name: 5 Rena Rowan Breast Center, University of Pennsylvania, Philadelphia, PA 19104-1693, USA – name: 4 Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA – name: 3 Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA – name: 6 Abramson Cancer Center Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-1693, USA – name: 7 Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina |
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Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina – sequence: 3 givenname: Nikolaos surname: Svoronos fullname: Svoronos, Nikolaos organization: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA. Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. 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. Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina – sequence: 4 givenname: Michael J. surname: Allegrezza fullname: Allegrezza, Michael J. organization: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA. Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. 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. Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina – sequence: 5 givenname: Amelia J. surname: Tesone fullname: Tesone, Amelia J. organization: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA. Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. 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. 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Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina – sequence: 11 givenname: Rugang surname: Zhang fullname: Zhang, Rugang organization: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA. Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. 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. Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina – sequence: 12 givenname: Mariana surname: Salatino fullname: Salatino, Mariana organization: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA. Gene Expression and regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. 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. 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Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME-CONICET); Buenos Aires, Argentina |
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| Snippet | The dominant
TLR5
R392X
polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant... |
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| Title | MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION |
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