Periodontitis Promotes OSCC and Prostate Cancer Progression and Immunosuppression by Skewing Myeloid Differentiation of HSPCs

Abstract

Inflammation is an enabling characteristic that contributes to the acquisition of hallmarks of cancer. Epidemiological studies have suggested a potential connection between periodontitis and increased risk of cancer. However, the underlying mechanisms of this connection remain insufficiently studied. Here, we found that periodontitis promoted the progression of oral squamous cell carcinoma and prostate cancer and fostered an immunosuppressive tumor microenvironment (iTME) characterized by expanded myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and regulatory T cells in mouse models. Periodontitis also enhanced the immunosuppressive function of MDSCs and decreased the infiltration of CD8+ T cells. Moreover, periodontitis-induced systemic inflammation remodeled the bone marrow (BM) ecosystem, resulting in myeloid-biased hematopoiesis, which was accompanied by expansion of hematopoietic progenitors (LSK), multipotent progenitor 3 (MPP3), and granulocyte-monocyte precursors, followed by the subsequent augmentation of myeloid cell production. Mechanistically, interleukin (IL)–1 signaling, triggered by periodontitis, induced alterations in the myelopoiesis program. The conditional inhibition of IL-1R1 in the BM attenuated the tumor-promoting effect of periodontitis, diminished abnormal myeloid overproduction, and improved the TME. Thus, these findings reveal that periodontitis remotely induces a myeloid bias in hematopoietic stem and progenitor cells, and that the IL-1–mediated periodontitis–BM axis serves as a critical mechanism for periodontitis-facilitated tumor development and iTME establishment.

Graphical Abstract