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

Abstract

The dominant TLR5R392X 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.

Inflammation and skeletal metastasis

“…100 An intriguing report illustrates how a common mutation in the TLR5 occurring in 7.5% of humans influences cancer growth via tumor-related inflammation. 104 The use of a genetic mouse model of sarcoma tumorigenesis commensal bacteria promoted distal tumor progression through TLR5-mediated increase in systemic IL-6 levels. In turn, IL-6 stimulated the mobilization and expansion of MDSCs and the tumor infiltration of gdT cells that secreted galectin-1.…”

“…105 Further analysis showed similar results in a murine model of ovarian cancer, whereas TLR5 loss of function accelerated tumor growth in a model of IL-6 unresponsive breast cancer cells via an increase in systemic IL-17 mediated also by the commensal microbiota. 104 Therefore, TLR5 signaling regulates systemic inflammation and immune responses resulting in cancer suppression or progression.…”

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

“…Previous studies have reported pro-tumorigenic effects for different TLRs, such as TLR2 14–18 , TLR4 19–23 , TLR5 24 , TLR7 10,11,25 and TLR9 26–30 . In prostate and breast cancer, the stimulation of TLR9 induced an over-expression of matrix metalloproteinase 13 as well as an increase of cell invasion 31,32 .…”

Microbiote intestinal et réponses aux thérapies anti-tumorales

“…Plus récemment, la signalisation impliquant le récepteur TLR5, qui reconnaît la flagelline des bactéries, activée par la flore intestinale, a été associée à l'expansion de cellules myéloïdes suppressives (MDSC) au sein du microenvironnement tumoral. Stimulées par le microbiote, ces cellules vont, par l'intermédiaire des cellules T inhiber les réponses anti-tumorales et impacter la croissance de tumeurs du sein et de l'ovaire [23].…”