Oral Pathobiont Promoting Both Immune Suppression and Direct Oncogenesis

Objectives: Chronic periodontitis (CP) is a microbially induced dysbiotic disease linked to increased risk for oral squamous cell carcinomas (OSCCs) and oropharyngeal cancers, however, the mechanisms are unclear. The main objective of this study is to investigate the molecular mechanisms of oral dysbiosis, particularly pathways involved in cancer genesis, induced by the oral Pathobiont Porphyromonas gingivalis and its fimbrial mutants.
Methods: To address the underlying mechanisms in this link, we utilized different animal models, human monocyte-derived DCs (MoDCs), OSC-epithelial cells in-vitro, combined with ex-vivo-isolated blood myeloid dendritic cells (mDCs) and gingival specimens from CP subjects and healthy controls.
Results: Our results shows, the 'keystone' pathogen Porphyromonas gingivalis, through its mfa-1 fimbrial adhesin, disrupts immune surveillance, by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3+T_regs through anti-apoptotic pathway. This pathway, involving induction of pAKT1, pFOXO1, FOXP3, IDO1 and downregulation of BIM is activated in humans with CP and in mice orally infected with mfa1+ P.gingivalis. ChIP assay further established activation of this pathway and delineated FOXP3 as a direct FOXO1 target gene in human CP gingival tissues. Expression of oncogenic (CXCR4, VEGF) but not tumor-suppressor (LDOC1, FOXO3) markers support a direct effect on tumor growth, as demonstrated in OSCCs co-cultured with P. gingivalis. Importantly, we further demonstrate that fimA adheres, invades, and induces angiogenesis, oncogenic genes and proteins to stimulate growth of OSCC through their unique CXCR4, whereas inhibitors completely abolish Pg-strains-induced OSCC cell growth and oncogenic responses.
Conclusions: We conclude that blocking the DC-SIGN^+hi/CXCR4^+hi pAKT^+hi pFOXO1^+hi BIM^-low FOXP3^+hi and IDO^+hi- driven oncogenic pathway may be the key to restoring immune surveillance and homeostasis in chronic dysbiotic infections such as periodontitis.