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

被引:20
|
作者
Ren, Junling [1 ]
Han, Xiao [1 ]
Lohner, Hannah [1 ]
Hoyle, Rosalie G. [2 ,3 ]
Li, Jiong [2 ,3 ]
Liang, Shuang [4 ]
Wang, Huizhi [1 ,5 ,6 ]
机构
[1] Virginia Commonwealth Univ, VCU Philips Inst Oral Hlth Res, Dept Oral & Craniofacial Mol Biol, Richmond, VA USA
[2] Virginia Commonwealth Univ, Inst Struct Biol Drug Discovery & Dev, Richmond, VA USA
[3] Virginia Commonwealth Univ, VCU Sch Pharm, Dept Med Chem, Richmond, VA USA
[4] NYU, Coll Dent, Dept Mol Pathobiol, New York, NY USA
[5] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA
[6] Virginia Commonwealth Univ, Dept Oral & Craniofacial Mol Biol, 521 N 11TH, Richmond, VA 23298 USA
关键词
IMMUNOTHERAPY; GENERATION; MPDL3280A;
D O I
10.1158/2326-6066.CIR-22-0541
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:290 / 305
页数:16
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