Common TLR5 Mutations Control Cancer Progression
Authors: Christina Pfirschke, Christopher Garris, Mikael J. Pittet
Journal: Cancer Cell (2015)

The mechanisms regulating tumor-associated inflammation are incompletely understood. In this issue of Cancer Cell, Rutkowski and colleagues indicate that TLR5 signaling deficiency, which occurs in ∼10% of the population, changes interactions with commensal microbiota and deregulates a cascade of inflammatory events that can suppress or accelerate extraintestinal cancers. The mechanisms regulating tumor-associated inflammation are incompletely understood. In this issue of Cancer Cell, Rutkowski and colleagues indicate that TLR5 signaling deficiency, which occurs in ∼10% of the population, changes interactions with commensal microbiota and deregulates a cascade of inflammatory events that can suppress or accelerate extraintestinal cancers. Cancer and inflammation were first linked more than 150 years ago by Robert Virchow, who observed that leukocytes frequently infiltrate tumors. Yet, the role of the immune system in malignancy has only recently come under more extensive study. At present, we understand that distinct immune components, which define a so-called immune contexture (Fridman et al., 2012Fridman W.H. Pagès F. Sautès-Fridman C. Galon J. Nat. Rev. Cancer. 2012; 12: 298-306Crossref PubMed Scopus (3102) Google Scholar), can either repress or promote cancer. Recent evidence also indicates that intestinal commensal bacteria profoundly influence immune cell activity in health and disease (Hooper et al., 2012Hooper L.V. Littman D.R. Macpherson A.J. Science. 2012; 336: 1268-1273Crossref PubMed Scopus (2681) Google Scholar) and modulate disease-associated immune responses to therapy even at extraintestinal sites (Iida et al., 2013Iida N. Dzutsev A. Stewart C.A. Smith L. Bouladoux N. Weingarten R.A. Molina D.A. Salcedo R. Back T. Cramer S. et al.Science. 2013; 342: 967-970Crossref PubMed Scopus (1314) Google Scholar, Viaud et al., 2013Viaud S. Saccheri F. Mignot G. Yamazaki T. Daillère R. Hannani D. Enot D.P. Pfirschke C. Engblom C. Pittet M.J. et al.Science. 2013; 342: 971-976Crossref PubMed Scopus (1238) Google Scholar). Therefore, uncovering which microbiota-host interactions cause or prevent disease should increase our understanding of cancer and possibly offer new vantage points for therapy. In this issue of Cancer Cell, Rutkowski et al., 2015Rutkowski M.R. Stephen T.L. Svoronos N. Allegrezza M.J. Tesone A.J. Perales-Puchalt A. Brencicova E. Escovar-Fadul X. Nguyen J.M. Cadungog M.G. et al.Cancer Cell. 2015; 27 (this issue): 27-40Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar report that Toll-like receptor 5 (TLR5), a pattern recognition receptor that recognizes bacteria-derived products, can greatly affect extraintestinal tumor progression through differential modulation of systemic inflammation and tumor-associated immunity. The findings presented in this study might have broad consequences, because TLR5 loss-of-function mutations are frequent in humans (Casanova et al., 2011Casanova J.-L. Abel L. Quintana-Murci L. Annu. Rev. Immunol. 2011; 29: 447-491Crossref PubMed Scopus (269) Google Scholar). Using a conditional genetic mouse model of sarcoma driven by Kras and Trp53 alterations, Rutkowski et al., 2015Rutkowski M.R. Stephen T.L. Svoronos N. Allegrezza M.J. Tesone A.J. Perales-Puchalt A. Brencicova E. Escovar-Fadul X. Nguyen J.M. Cadungog M.G. et al.Cancer Cell. 2015; 27 (this issue): 27-40Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar initially found that TLR5 deficiency decreased systemic interleukin 6 (IL-6) serum levels and delayed tumor progression. In this model IL-6 also controlled myeloid cell mobilization, which is associated with accelerated tumor progression, according to previous studies (Gabrilovich et al., 2012Gabrilovich D.I. Ostrand-Rosenberg S. Bronte V. Nat. Rev. Immunol. 2012; 12: 253-268Crossref PubMed Scopus (2522) Google Scholar). Interestingly, depleting commensal microbiota by orally administering antibiotics to TLR5-responsive mice was sufficient to control IL-6 levels, myeloid cell mobilization, and sarcoma outgrowth. Bacterial depletion also prevented accumulation of tumor-infiltrating γδ T cells, which can mediate immunosuppressive functions and promote cancer progression (Peng et al., 2007Peng G. Wang H.Y. Peng W. Kiniwa Y. Seo K.H. Wang R.-F. Immunity. 2007; 27: 334-348Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Separate experiments involving antibody-mediated depletion or adoptive transfer of γδ T cells further indicated that the presence of this T cell subset accelerates malignant progression in TLR5-responsive hosts. These data show that TLR5-mediated host recognition of commensal bacteria can regulate tumor progression by affecting the tumor's immune contexture. Rutkowski and colleagues further report that, in the presence of commensal bacteria, γδ T cells produce the immunosuppressive molecule galectin-1 (Rubinstein et al., 2004Rubinstein N. Alvarez M. Zwirner N.W. Toscano M.A. Ilarregui J.M. Bravo A. Mordoh J. Fainboim L. Podhajcer O.L. Rabinovich G.A. Cancer Cell. 2004; 5: 241-251Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar), thereby suggesting that microbiota also affect the functions of tumor-associated immune cells. Mechanistic studies indicate that myeloid cells can produce adenosine, which helps upregulate galectin-1 expression in γδ T cells. Also, by generating chimeras with γδ- and galectin-1-deficient bone marrow, the authors found that galectin-1 secreted by γδ T cells is sufficient to accelerate Kras/p53-driven sarcoma growth in mice. Rutkowski et al., 2015Rutkowski M.R. Stephen T.L. Svoronos N. Allegrezza M.J. Tesone A.J. Perales-Puchalt A. Brencicova E. Escovar-Fadul X. Nguyen J.M. Cadungog M.G. et al.Cancer Cell. 2015; 27 (this issue): 27-40Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar went on to assess consequences of TLR5 loss-of-function in mouse models of other extraintestinal cancers and found that TLR5 deficiency does not always suppress tumor growth. In fact, they determined that the A7C11 breast carcinoma cell line grows even faster in TLR5-deficient hosts than in their wild-type counterparts. The precise mechanisms that dictate whether TLR5 signaling will promote or suppress cancer require further study, yet initial findings indicate that cytokines can play a role. In TLR5-sufficient mice, several tumors (e.g., the MPKAS cell line derived from axillary tumors of the genetic Kras/Trp53 mouse model and orthotopic ovarian cancers) increased systemic IL-6 serum levels and likely depended on IL-6 to grow, whereas A7C11 breast tumors did not. Instead, A7C11-bearing mice showed increased IL-17 serum levels in TLR5-deficient mice. Administering IL-17 blocking antibodies controlled A7C11 tumor progression. Also, commensal bacteria depletion in these mice reduced IL-17 levels and controlled tumor growth. Administering IL-17 blocking antibodies also controlled MPKAS tumor growth, but only when IL-6 was also blocked. Taken together, the murine data suggest that IL-6 and IL-17 differ in their ability to influence tumor-promoting inflammation; IL-6 may be induced preferentially in TLR5-competent hosts by the TLR itself and then drive malignant progression, whereas IL-17 may increase malignant progression only in the absence of both IL-6 and functional TLR5 signaling. Yet, both IL-6 and IL-17 are affected by commensal microbiota and eventually drive systemic changes that impact the immune contexture and foster tumor progression. That microbiota-TLR5 interactions in mice control systemic inflammation and cancer might also be relevant for breast and ovarian cancer patients (Figure 1). Tumors from breast cancer patients with TLR5R392x have higher IL-17A transcript levels than those homozygous for the wild-type TLR5 allele. Retrospective analysis revealed that TLR5R392x breast cancer patients may have poorer overall survival compared to patients with wild-type TLR5 alleles. In contrast, retrospective analysis indicated that TLR5R392X ovarian cancer patients may have improved survival. This is consistent with mouse model data indicating that TLR5 signaling can accelerate ovarian cancer progression. As in the murine studies, TLR5-responsive ovarian cancer patients showed higher systemic IL-6 levels, whereas TLR5-unresponsive patients showed decreased numbers of γδ T cells and myeloid cells in the tumor stroma. All in all, ovarian cancer seems more IL-6 dependent in the presence of functional TLR5 signaling, whereas breast cancer may be preferentially driven by IL-17 in the absence of functional TLR5 (Figure 1). However, the relevance of, and dependence on, systemic IL-6 and IL-17 cytokines during tumor progression will require follow-up studies. Interestingly, intestinal bacterial populations can regulate host immunity not only locally, but also systemically (Hooper et al., 2012Hooper L.V. Littman D.R. Macpherson A.J. Science. 2012; 336: 1268-1273Crossref PubMed Scopus (2681) Google Scholar, Ichinohe et al., 2011Ichinohe T. Pang I.K. Kumamoto Y. Peaper D.R. Ho J.H. Murray T.S. Iwasaki A. Proc. Natl. Acad. Sci. USA. 2011; 108: 5354-5359Crossref PubMed Scopus (980) Google Scholar), but we do not yet know whether, or to what extent, certain intestinal microbial species define the immune contexture of, e.g., extraintestinal tumors. The present study indicates that the microbiome from Tlr5–/– mice cannot be transferred to co-housed wild-type mice, thereby suggesting that wild-type mice exhibit colonization resistance to the transferred bacteria. Instead, transplanting microbiota from Tlr5–/– mice to germ-free recipients may overcome colonization resistance barriers and facilitate mechanistic studies of specific microbes and their association with immune contexture and cancer development. Specific associations between microbiota and tumor immune contexture could provide a proxy for assaying the human tumor microenvironment by characterizing microbial species in the human intestines. The human tumor microenvironment is very difficult to characterize in vivo, so sequencing human microbiomes would be a convenient means to provide critical patient information. Whether TLR5 loss-of-function can affect responses to anticancer therapy also remains unknown. Because the intestinal commensal microbiota can impact chemotherapy and immunotherapy (Viaud et al., 2013Viaud S. Saccheri F. Mignot G. Yamazaki T. Daillère R. Hannani D. Enot D.P. Pfirschke C. Engblom C. Pittet M.J. et al.Science. 2013; 342: 971-976Crossref PubMed Scopus (1238) Google Scholar, Iida et al., 2013Iida N. Dzutsev A. Stewart C.A. Smith L. Bouladoux N. Weingarten R.A. Molina D.A. Salcedo R. Back T. Cramer S. et al.Science. 2013; 342: 967-970Crossref PubMed Scopus (1314) Google Scholar) and TLR5-deficiency perturbs the microbiota, the altered microbiota in a TLR5-deficient setting could also affect responses to treatment. Follow-up work examining how TLR5 signaling deficiency alters drug-induced immune responses and effective cancer control could prove valuable in personalizing cancer treatments. Because TLR5 is one of many innate immune regulators, evaluating common deficiencies or polymorphisms in other innate immune pathways could also provide insight into the mechanisms regulating systemic inflammation and influencing tumor growth and response to therapy. Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting InflammationRutkowski et al.Cancer CellDecember 18, 2014In BriefRutkowski et al. find that commensal bacteria promote systemic inflammation through TLR5, resulting in impaired antitumor immunity and accelerated progression of extramucosal tumors. They identify unique effects dependent on the ability of tumor cells to respond to IL-6 and implicate IL-17 in IL-6-nonresponsive tumors. Full-Text PDF Open Archive