PD-L1 Up-Regulation in Prostate Cancer Cells by Porphyromonas gingivalis

Abstract

Chronic inflammation is known to contribute to various human cancers. Porphyromonas gingivalis (P. gingivalis), is a gram-negative oral keystone pathogen that may cause severe periodontitis and expresses several virulence factors to affect the host immune system. Periodontitis is a chronic infectious disease that while progression, may cause loss of attachment and destruction of the tooth supporting tissues. Prostate cancer is one of the most common malignancies in men. Increasing evidence links periodontitis with prostate cancer, however the mechanisms explaining this relationship remain unclear. The aim of this study was to investigate the expression and signaling pathway of programmed death ligand 1 (PD-L1) in a prostate cancer cell line after infection with P. gingivalis and stimulation with P. gingivalis components to reveal the mechanism of tumor-induced immune evasion associated with bacterial infection in the tumor environment. Prostate cancer cells were infected with different concentrations of viable P. gingivalis and treated with different concentrations of heat-killed P. gingivalis and P. gingivalis cell components, including the total membrane fraction, inner membrane fraction, outer membrane fraction, cytosolic fraction and peptidoglycan (PGN). Chemical inhibitors were used to block different important molecules of signaling pathways to assess the participating signal transduction mechanisms. PD-L1 expression was detected by Western blot after 24 h of infection. PD-L1 was demonstrated to be upregulated in prostate cancer cells after infection with viable and with heat-killed P. gingivalis membrane fractions. Also isolated PGN induced PD-L1 up-regulation. The upregulation was mediated by the NOD1/NOD2 signaling pathway. No upregulation could be detected after treatment of the cells with P. gingivalis lipopolysaccharide (LPS). These results indicate, that chronic inflammatory disease can contribute to tumor immune evasion by modifying the tumor microenvironment. Thus, chronic infection possibly plays an essential role in the immune response and may promote the development and progression of prostate cancer.

Promising dawn in tumor microenvironment therapy: engineering oral bacteria

“… 183 , 184 In animal tumor-bearing experiments, samples infected with P. gingivalis in the tumor microenvironment exhibited the highest levels of cell invasion and proliferation, as well as the largest tumor volume. 185 Similar results have also been observed in colorectal cancer, 186 prostate cancer, 187 and pancreatic cancer. 188 …”

“… 211 For instance, PD-L1 was demonstrated to be upregulated in prostate cancer cells after infection with P. gingivalis membrane fractions by the NOD1/NOD2 signaling pathway. 187 Moreover, it found that P. gingivalis infection elicited the elevation of PD-L1 expression on dendritic cells (DCs) through the Akt-STAT3 signaling pathway, thereby dampening CD8+ T-cell cytotoxicity and exacerbating the growth of oral cancer cells. 212 Additionally, P. gingivalis could inhibit PDCD4 (programmed cell death factor 4) expression and lead to cancer stem cells (CSCs) enrichment in ESCC cells.…”

NOD1 and NOD2 Are Potential Therapeutic Targets for Cancer Immunotherapy

“…Porphyromonas gingivalis is an oral keystone pathogen that causes severe periodontitis by interfering with the host's immunological homeostasis. Furthermore, it has been shown that PD-L1 was increased via the NOD1/NOD2 pathway in prostate cancer cells following infection with Porphyromonas gingivalis, indicating that chronic inflammation can promote tumor metastasis by changing the tumor microenvironment [ 33 ].…”

“…However, the role of NOD1 and NOD2 in cancer is complicated, indicating that more studies in this field are necessary. It has been found that NOD1 activation contributes to tumor suppression mainly through RIP2/TAK1/ MAPK pathway-mediated apoptosis in oral cancer [45], thyroid cancer [23], breast cancer [26], and GC 27, whereas NOD1 overexpression is associated with tumor development with decreased chemotherapy sensitivity but enhanced immunosuppression in HNSCC 24, ESCC25, prostate cancer [33], and ovarian cancer [36]. Based on those studies, we examined the conflicting roles of NOD1 in HCC [28,29], CRC [22,[30][31][32], and cervical cancer [34,35] and found that NOD1-regulated apoptotic activation is a common feature in tumor suppression, whereas NOD1-mediated immunosuppression is another comparable characteristics in NOD1promoted malignancy which has been described by several studies [31,32].…”

PD-L1, a Potential Immunomodulator Linking Immunology and Orthodontically Induced Inflammatory Root Resorption (OIIRR): Friend or Foe?

“…It was reported that high levels of PD-L1 are expressed in many tumor cells [ 19 ]. In vivo, its expression was demonstrated in the tissue of oral squamous carcinoma cells [ 20 ], human colon carcinoma cells [ 21 ], and human prostate cancer cells [ 22 ]. PD-L1 exerts immunosuppressive effects on the immune response of the host; thus, its expression strongly may limit anti-tumor treatment efficacy [ 23 ].…”