Abstract
Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.
Highlights
While this myeloid cell type functionally resembles myeloid-derived suppressor cells (MDSCs), which have been associated with oncogenesis[22,43], these are phenotypically a distinct subtype of immature Dendritic cells (DCs) (CD14lowCD83−CD1c+Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN)+) which we provisionally call Myeloid Derived Dendritic Suppressor Cells (MDDSCs)
P. gingivalis[381], which expresses both Mfa[1] and FimA, induced T-cell suppression factors programmed death-ligand-1 (PD-L1 or CD274), IL-10, adenosine A2b receptor (ADORA2B), ICOS Ligand (CD275) involved in recruitment of T-cells into oral mucosal tissues, and IDO1, CD80 involved in immunosuppressive activities of MDSCs compared with uninfected control monocyte-derived DCs (MoDCs)
It’s worth noting that the cell proliferation and oncogenic gene AKT1, angiogenic molecule VEGF-A, immunosuppressive molecule IDO1, IL-10, the transcription factor STAT3 were highly upregulated (≥20 FPKM), whereas pro-apoptotic/cell death related genes BIM, BAD, CASP8 were down-regulated in DPG3 compared with P. gingivalis381 (Pg381)
Summary
The induction of apoptosis in host cells and in their prompt removal by phagocytes is important for maintaining tissue homeostasis This is important for the development of an immunogenic response and antitumor immunity. Inhibition of apoptosis is mediated by downstream effectors of serine-threonine protein kinase- (Akt1) and Bcl-2 family members[31] This anti-apoptotic pathway is activated in DCs by many factors including ligation of DC-SIGN32. The mechanistic role of FOXO1/pFOXO1 in regulating myeloid cell plasticity and immune homeostasis in response to this pathogen is unknown. Combined with our evidence for direct induction of OSCCs proliferation by P. gingivalis, we conclude that blocking this pathway is a promising interventional approach to restore immune-surveillance and reduce oncogenic cell proliferation in dysbiotic conditions such as periodontitis
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