Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells

Abstract

Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

“…For example, the CCL5/CCR5 axis, which can recruit CD4 + and CD8 + T cells [77] and NK cells [42], can predict the improved efficiency of DC-immunotherapy in NSCLC [78]. Nevertheless, this pair also exhibits chemoattraction to TAMs and MDSCs [79,80], and has been reported to correlate with poor outcomes in BC patients [81].…”

“…The CCL5/CCR5 axis has been demonstrated to promote cancer cell migration through the recruitment and modulation of inflammatory cell activities, followed by the generation of an immunosuppressive environment including TAMs and MDSCs in BC [79,80,161]. Data from a study on BC patients showed that patients with higher serum levels of CCL5 had a greater probability of lymph node metastasis [81].…”

Surgical trauma‐induced immunosuppression in cancer: Recent advances and the potential therapies

“…Besides promoting the expansion of MDSCs, proinflammatory cytokines released after tissue damages including IL‐6, TGF‐β, and IL‐10 activate inflammatory signaling cascades including MyD88 and the transcriptional factor NF‐κB 108,109 . The following activated IL‐1β associated with increased secretion of CCLs or CXCLs that responsible for monocytic‐MDSCs (M‐MDSCs) and granulocytic‐MDSCs (G‐MDSC) accumulation, respectively 110 . In addition, prostaglandin E2 (PGE‐2) 111,112 and TNF signal 113 also involved in the process of MDSCs accumulation.…”

“…Anakinra is an IL‐1 receptor antagonist with the potential to inhibit distal metastasis via pyroptosis/IL‐1β pathways blockade. Administration of anakinra reduced the recruitment of M2‐macrohages and MDSCs via downregulation of CCL2, CCL5, and CXCL5 secretion 110 . Inhibitors specific to NLRP3 inflammasome may be the best option for therapy of NLRP3‐related disease.…”

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance

“…TLR4 is reported to be expressed in skin and lung fibroblasts (33,34). Recently, we reported the expression of TLR2 and TLR4 activity in gingival fibroblastic cells (35). However, endosomal TLR9 is described in macrophage and dendritic cells signal in response to unmethylated bacterial DNA for the initiation of an inflammasome signaling cascade associated with IL-1β and IL-6 expression (36).…”