title: Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.
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.
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Svoronos
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tesone
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Brencicova
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Ximena
authors.initials: X
authors.lastname: Escovar-Fadul
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Cadungog
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Salatino
authors.affiliation: 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.
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D037483:Galectin 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064307:Microbiota; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D037483:Galectin 1; D020381:Interleukin-17; D015850:Interleukin-6; D051198:Toll-Like Receptor 5