P. gingivalis Infection Upregulates PD-L1 Expression on Dendritic Cells, Suppresses CD8+T-cell Responses, and Aggravates Oral Cancer

Accumulating evidence shows that PD-L1 expression on den-dritic cells (DC) is critical for cancer immunotherapy and that Porphyromonas gingivalis (Pg) colonization aggravates the pro-gression of upper gastrointestinal cancers. However, the effects of Pg infection on PD-L1 expression on DCs and related immune consequences in the infection milieu of oral cancer remain unexplored. Here, we found that Pg infection robustly enhanced PD-L1 expression on DCs in a gingipain-dependent manner in cultured cell and systemic infection assays. Pg infection sup -pressed antigen-specific CD8+ T cells through upregulation of PD-L1 expression on ovalbumin (OVA)-pulsed DCs. This sup -pression was manifested by decreased IFNy, perforin, granzyme B, and CD107a. Further analysis showed that Pg drastically reduced CD8+ T cells' ability to lyse OVA-pulsed target cells. Additionally, Pg infection increased the phosphorylation of Akt and STAT3, leading to a significant increase in PD-L1 expression. This was substantiated by using siRNA, overexpression plasmids, and pharmacologic inhibitors. Consistent with the in vitro obser-vations, in a syngeneic mouse oral cancer model, Pg infection significantly enhanced PD-L1 expression on DCs from intratu-moral tissues and cervical lymph nodes and exacerbated oral cancer progression, whereas a Pg lysine-specific, gingipain-defective mutant failed to do so. These influences of Pg were largely diminished when tumor cells were pretreated with anti-biotics or a STAT3 inhibitor. Therefore, we demonstrated that Pg infection upregulates PD-L1 expression on DCs through Akt-STAT3 signaling, suppresses CD8+ T-cell cytotoxicity, and aggravates oral cancer growth, suggesting targeting Pg, and/or its mediated signaling, could be a therapeutic strategy to improve the efficacy of checkpoint blockade immunotherapy.