Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer

• Published in: Cell death & disease Vol. 12; no. 11; pp. 1033 - 14
• Main Authors: Yin, Hanlin, Pu, Ning, Chen, Qiangda, Zhang, Jicheng, Zhao, Guochao, Xu, Xuefeng, Wang, Dansong, Kuang, Tiantao, Jin, Dayong, Lou, Wenhui, Wu, Wenchuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/51; 13/89; 38; 38/77; 45/15; 631/67/1059/2325; 631/67/327; 64/60; 82/80; Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Aged; AKT protein; Animals; Antibodies; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biochemistry; Biomedical and Life Sciences; Cancer therapies; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell activation; Cell Biology; Cell Culture; Cytotoxicity; Dendritic cells; Disease Models, Animal; Female; Gastrointestinal Tract - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Evasion - drug effects; Immune system; Immune Tolerance - drug effects; Immunological tolerance; Immunology; Inflammation; Inflammatory bowel disease; Life Sciences; Lipopolysaccharides; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Male; Medical prognosis; Metastases; Mice; Mice, Inbred BALB C; Models, Biological; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - metabolism; NF-κB protein; Pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PD-L1 protein; Permeability; Proto-Oncogene Proteins c-akt - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Synergism; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription; Transcription, Genetic - drug effects; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04293-4

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.