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.
Highlights
pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that causes the fourth leading cancer-related death with the lowest 5-year survival rate compared with other cancers [1]
programmed death ligand-1 (PD-L1) is an important negative immune molecular that participates in host immunity homeostasis, and tumor-associated PD-L1 promotes tumor immune escape by combining with PD-1 on tumor-infiltrating lymphocytes (TILs) and inducing their exhaustion and apoptosis [4]
PDAC has been documented as a nonimmunogenic tumor and low lymphocyte infiltration, which could be one of the explanations for its resistance to immune checkpoint blockade (ICB)
Summary
Gut-derived LPS was detected in PDAC and influenced tumor in tumor tissues. Tumoral LPS was detected by immunochemistry staining as TLR4 expression was higher in PDAC tumor tissues, which previously reported [21]. Containing 16 PDAC patients showed that the intestinal barrier Immunochemistry staining further verified that TLR4 was overmarker - serum zonulin had a positive correlation with serum LPS expressed in PDAC cancer cells when compared to adjacent in PDAC patients, which indicated that the increased intestinal pancreatic ductal cells (Fig. 3C). Orthotopic tumor tissues after 7 days of DSS treatment (Fig. 1I) These results revealed that gut leakage might increase serum LPS found to have a significant correlation with PD-L1 by analyzing and promote LPS deposition in PDAC tissues. Further [25, 26], we analyzed TILs by immunochemistry staining and found analyses showed that both LPS/HDL (Fig. 3H) and LBP (Fig. 3I) had that tumor-infiltrating CD3+ and CD8+ T cell significantly a positive correlation with tumoral PD-L1 These showed that increased after LPS treatment (Fig. 2B).
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