Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer
Abstract Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04293-4 |
| _version_ | 1798035174247628800 |
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| author | Hanlin Yin Ning Pu Qiangda Chen Jicheng Zhang Guochao Zhao Xuefeng Xu Dansong Wang Tiantao Kuang Dayong Jin Wenhui Lou Wenchuan Wu |
| author_facet | Hanlin Yin Ning Pu Qiangda Chen Jicheng Zhang Guochao Zhao Xuefeng Xu Dansong Wang Tiantao Kuang Dayong Jin Wenhui Lou Wenchuan Wu |
| author_sort | Hanlin Yin |
| collection | DOAJ |
| description | Abstract Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC. |
| first_indexed | 2024-04-11T20:54:36Z |
| format | Article |
| id | doaj.art-4144d0bf664a42c0ab804c74e75fe128 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T20:54:36Z |
| publishDate | 2021-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-4144d0bf664a42c0ab804c74e75fe1282022-12-22T04:03:43ZengNature Publishing GroupCell Death and Disease2041-48892021-10-01121111410.1038/s41419-021-04293-4Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancerHanlin Yin0Ning Pu1Qiangda Chen2Jicheng Zhang3Guochao Zhao4Xuefeng Xu5Dansong Wang6Tiantao Kuang7Dayong Jin8Wenhui Lou9Wenchuan Wu10Department of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityAbstract Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.https://doi.org/10.1038/s41419-021-04293-4 |
| spellingShingle | Hanlin Yin Ning Pu Qiangda Chen Jicheng Zhang Guochao Zhao Xuefeng Xu Dansong Wang Tiantao Kuang Dayong Jin Wenhui Lou Wenchuan Wu Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer Cell Death and Disease |
| title | Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer |
| title_full | Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer |
| title_fullStr | Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer |
| title_full_unstemmed | Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer |
| title_short | Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer |
| title_sort | gut derived lipopolysaccharide remodels tumoral microenvironment and synergizes with pd l1 checkpoint blockade via tlr4 myd88 akt nf κb pathway in pancreatic cancer |
| url | https://doi.org/10.1038/s41419-021-04293-4 |
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