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IL-17 mediates susceptibility to breast cancer growth by promoting the recruitment of tumorigenic neutrophils

ABSTRACT: The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL-17 levels. In this study, we investigated the role of IL-17 in invasive breast tumor pathogenesis. We found that metastatic tumor-infiltrating T lymphocytes produced elevated levels of IL-17, whereas IL-17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, and their depletion suppressed tumor growth. Moreover, IL-17 induced IL-6 and CXCL1 production in tumor cells, and IL-6 depletion reduced metastatic tumor growth and infiltration by Th17 cells and neutrophils. In addition, inoculation of a non-metastatic mammary tumor cell line pre-incubated with IL-17 promoted tumor growth, confirming the pro-tumor role of IL-17. Furthermore, high IL-17 expression was associated with lower disease-free survival (DFS) and worse prognosis in IDC patients. Thus, IL-17 blockade represents an attractive approach for the control of invasive breast tumors. Biopsies of patients with breast tumors

ORGANISM(S): Homo sapiens

SUBMITTER: De Carvalho Daniel

PROVIDER: S-ECPF-GEOD-56822 | biostudies-other |

REPOSITORIES: biostudies-other

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IL-17 mediates susceptibility to breast cancer growth by promoting the recruitment of tumorigenic neutrophils

Project description:The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL-17 levels. In this study, we investigated the role of IL-17 in invasive breast tumor pathogenesis. We found that metastatic tumor-infiltrating T lymphocytes produced elevated levels of IL-17, whereas IL-17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, and their depletion suppressed tumor growth. Moreover, IL-17 induced IL-6 and CXCL1 production in tumor cells, and IL-6 depletion reduced metastatic tumor growth and infiltration by Th17 cells and neutrophils. In addition, inoculation of a non-metastatic mammary tumor cell line pre-incubated with IL-17 promoted tumor growth, confirming the pro-tumor role of IL-17. Furthermore, high IL-17 expression was associated with lower disease-free survival (DFS) and worse prognosis in IDC patients. Thus, IL-17 blockade represents an attractive approach for the control of invasive breast tumors. Biopsies of patients with breast tumors

2015-04-01 | E-GEOD-56822 | biostudies-arrayexpress

IL-17 mediates susceptibility to breast cancer growth by promoting the recruitment of tumorigenic neutrophils

2015-04-01 | GSE56822 | GEO

Interleukin 17 Receptor E (IL-17RE) and IL-17C Mediate the Recruitment of Neutrophils during Acute Streptococcus pneumoniae Pneumonia.

Project description:Neutrophils contribute to lung injury in acute pneumococcal pneumonia. The interleukin 17 receptor E (IL-17RE) is the functional receptor for the epithelial-derived cytokine IL-17C, which is known to mediate innate immune functions. The aim of this study was to investigate the contribution of IL-17RE/IL-17C to pulmonary inflammation in a mouse model of acute Streptococcus pneumoniae pneumonia. Numbers of neutrophils and the expression levels of the cytokine granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor alpha (TNF-?) were decreased in lungs of IL-17RE-de?cient (Il-17re-/- ) mice infected with S. pneumoniae Numbers of alveolar macrophages rapidly declined in both wild-type (WT) and Il-17re-/- mice and recovered 72?h after infection. There were no clear differences in the elimination of bacteria and numbers of blood granulocytes between infected WT and Il-17re-/- mice. The fractions of granulocyte-monocyte progenitors (GMPs) were significantly reduced in infected Il-17re-/- mice. Numbers of neutrophils were significantly reduced in lungs of mice deficient for IL-17C 24?h after infection with S. pneumoniae These data indicate that the IL-17C/IL-17RE axis promotes the recruitment of neutrophils without affecting the recovery of alveolar macrophages in the acute phase of S. pneumoniae lung infection.

| S-EPMC6803337 | biostudies-literature

IL-17-producing ?? T cells and neutrophils conspire to promote breast cancer metastasis.

Project description:Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1? elicits IL-17 expression from gamma delta (??) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of ?? T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of ?? T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system--the ?? T cell/IL-17/neutrophil axis--represents a new strategy to inhibit metastatic disease.

| S-EPMC4475637 | biostudies-literature

IL-17 mediates protective immunity against nasal infection with Bordetella pertussis by mobilizing neutrophils, especially Siglec-F<sup>+</sup> neutrophils.

Project description:Understanding the mechanism of protective immunity in the nasal mucosae is central to the design of more effective vaccines that prevent nasal infection and transmission of Bordetella pertussis. We found significant infiltration of IL-17-secreting CD4+ tissue-resident memory T (TRM) cells and Siglec-F+ neutrophils into the nasal tissue during primary infection with B. pertussis. Il17A-/- mice had significantly higher bacterial load in the nasal mucosae, associated with significantly reduced infiltration of Siglec-F+ neutrophils. Re-infected convalescent mice rapidly cleared B. pertussis from the nasal cavity and this was associated with local expansion of IL-17-producing CD4+ TRM cells. Depletion of CD4 T cells from the nasal tissue during primary infection or after re-challenge of convalescent mice significantly delayed clearance of bacteria from the nasal mucosae. Protection was lost in Il17A-/- mice and this was associated with significantly less infiltration of Siglec-F+ neutrophils and antimicrobial peptide (AMP) production. Finally, depletion of neutrophils reduced the clearance of B. pertussis following re-challenge of convalescent mice. Our findings demonstrate that IL-17 plays a critical role in natural and acquired immunity to B. pertussis in the nasal mucosae and this effect is mediated by mobilizing neutrophils, especially Siglec-F+ neutrophils, which have high neutrophil extracellular trap (NET) activity.

| S-EPMC8379078 | biostudies-literature

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17-Neutrophil Response.

Project description:The relationship established between Leishmania infantum and the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL-27), play a role in susceptibility to L. infantum infection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused by L. infantum We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL-27 production by macrophages. Furthermore, IL-27 plays a major regulatory role in vivo, because Ebi3(-/-) mice can efficiently control parasite replication despite reduced levels of IFN-? compared to wild-type mice. On the other hand, the absence of Ebi3 leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 during L. infantum infection. As a consequence of exacerbated IL-17A in Ebi3(-/-) mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production after L. infantum infection and demonstrated its regulatory role in the IL-17A-neutrophil axis.

| S-EPMC4962641 | biostudies-literature

IL-17 induces antitumor immunity by promoting beneficial neutrophil recruitment and activation in esophageal squamous cell carcinoma.

Project description:Interleukin (IL)-17 has been reported to play a controversial role in tumor immunity. Our previous studies showed that infiltration of IL-17-producing cells in esophageal squamous cell carcinoma (ESCC) induced tumor protective immunity by recruiting CD8+T lymphocytes, natural killer (NK) cells, and B lymphocytes into the tumor microenvironment. However, the mechanism of IL-17 regulation of tumor-associated neutrophils remains elusive in ESCC. In this study, we therefore evaluated the accumulation of myeloperoxidase (MPO)+ neutrophils and its association with IL-17-producing cells within ESCC tumor nests. We also investigated the effects of IL-17 on the recruitment and antitumor activity of neutrophils. MPO+ neutrophil infiltration was found to predict a favorable prognosis in ESCC patients and was positively correlated with IL-17+ cell density. IL-17 stimulated ESCC tumor cells to release more of the CXC chemokines CXCL2 and CXCL3, which are involved in neutrophil migration. Furthermore, IL-17 potentiates the direct killing capability of neutrophils by enhancing the production of cytotoxic molecules, including reactive oxygen species (ROS), MPO, TNF-related apoptosis-inducing ligand (TRAIL), and IFN-γ. Experiments in mice suggested that IL-17 alone might not affect tumor progression in the tumor-bearing host, but IL-17 can inhibit tumor growth by promoting beneficial neutrophil infiltration and activation at tumor sites. As emerging evidence indicates that targeting tumor-associated neutrophils is a strategy for antitumor therapy, our findings reveal a positive contribution of IL-17 to the modulation of neutrophil-mediated antitumor immunity in ESCC. This study provides further understanding of the mechanisms that selectively regulate functional activities of neutrophils, which may be critical for developing new tumor immunotherapy.

| S-EPMC5739574 | biostudies-literature

IL-17-CXC Chemokine Receptor 2 Axis Facilitates Breast Cancer Progression by Up-Regulating Neutrophil Recruitment.

Project description:Recent evidence suggests that interactions among proinflammatory cytokines, chemokines, and cancer cell-recruited neutrophils result in enhanced metastasis and chemotherapy resistance. Nonetheless, the detailed mechanism remains unclear. Our aim was to discover the role of IL-17, CXC chemokine receptor 2 (CXCR2) ligands, and cancer-associated neutrophils in chemotherapy resistance and metastasis in breast cancer. Mice were injected with Cl66 murine mammary tumor cells, Cl66 cells resistant to doxorubicin (Cl66-Dox), or Cl66 cells resistant to paclitaxel (Cl66-Pac). Higher levels of IL-17 receptor, CXCR2 chemokines, and CXCR2 were observed in tumors generated from Cl66-Dox and Cl66-Pac cells in comparison with tumors generated from Cl66 cells. Tumors generated from Cl66-Dox and Cl66-Pac cells had higher infiltration of neutrophils and T helper 17 cells. In comparison with primary tumor sites, there were increased levels of CXCR2, CXCR2 ligands, and IL-17 receptor within the metastatic lesions. Moreover, IL-17 increased the expression of CXCR2 ligands and cell proliferation of Cl66 cells. The supernatant of Cl66-Dox and Cl66-Pac cells enhanced neutrophil chemotaxis. In addition, IL-17-induced neutrophil chemotaxis was dependent on CXCR2 signaling. Collectively, these data demonstrate that the IL-17-CXCR2 axis facilitates the recruitment of neutrophils to the tumor sites, thus allowing them to play a cancer-promoting role in cancer progression.

| S-EPMC6943375 | biostudies-literature

CCR2 mediates increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17.

Project description:Post influenza bacterial pneumonia is associated with significant mortality and morbidity. Dendritic cells (DCs) play a crucial role in host defense against bacterial pneumonia, but their contribution to post influenza-susceptibility to secondary bacterial pneumonia is incompletely understood. WT and CCR2-/- mice were infected with 100 plaque forming units (pfu) H1N1 intranasally alone or were challenged on day 5 with 7?×?107 colony forming units (cfu) methicillin-resistant Staphylococcus aureus intratracheally. WT mice express abundant CCL2 mRNA and protein post-H1N1 alone or dual infection. CCR2-/- mice had significantly higher survival as compared to WT mice, associated with significantly improved bacterial clearance at 24 and 48?h (10-fold and 14-fold, respectively) post bacterial challenge. There was robust upregulation of IL-23 and IL-17 as well as downregulation of IL-27 expression in CCR2-/- mice following sequential infection as compared to WT mice, which was also associated with significantly greater accumulation of CD103+ DC. Finally, WT mice treated with a CCR2 inhibitor showed improved bacterial clearance in association with similar cytokine profiles as CCR2-/- mice. Thus, CCR2 significantly contributes to increased susceptibility to bacterial infection after influenza pneumonia likely via altered dendritic cell responses and thus, CCR2 antagonism represents a potential therapeutic strategy.

| S-EPMC6375750 | biostudies-literature

mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production.

Project description:It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of inflammatory bowel disease. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23R as well as rorc and ahr. Retinoid acid receptor-related orphan receptor ? t and aryl-hydrocarbon receptor differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. In addition, IL-23 induced the activation of mTOR in neutrophils. Blockade of the mTOR pathway inhibited IL-23-induced expression of rorc and ahr, as well as IL-17 and IL-22 production. By using a microbiota Ag-specific T cell-mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota Ag-specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by the mTOR pathway.

| S-EPMC4868807 | biostudies-literature

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