INVESTIGADORES
RABINOVICH Gabriel Adrian
artículos
Título:
MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION
Autor/es:
RUTKOWSKI, MELANIE R. ; STEPHEN, TOM L. ; SVORONOS N; ALLEGREZZA, MICHAEL J. ; TESONE, AMELIA J. ; PERALES-PUCHALT, ALFREDO ; BRENCICOVA, EVA ; ESCOVAR-FADUL, XIMENA ; NGUYEN, JENNY M. ; CADUNGOG, MARK G. ; ZHANG, RUGANG ; SALATINO MARIANA ; TCHOU, JULIA ; RABINOVICH, GABRIEL ADRIAN; CONEJO-GARCIA, JOSE R.
Revista:
CANCER CELL
Editorial:
CELL PRESS
Referencias:
Lugar: United States; Año: 2015 vol. 27 p. 27 - 40
ISSN:
1535-6108
Resumen:
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.