RRC ID 58117
Author Tsukamoto M, Imai K, Ishimoto T, Komohara Y, Yamashita YI, Nakagawa S, Umezaki N, Yamao T, Kitano Y, Miyata T, Arima K, Okabe H, Baba Y, Chikamoto A, Ishiko T, Hirota M, Baba H.
Title PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-α leads to poor pancreatic cancer prognosis.
Journal Cancer Sci
Abstract Immunotherapy using anti-PD-1/PD-L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD-L1 expression in PDAC cells. Among the various cytokines tested, tumor necrosis factor (TNF)-α upregulated PD-L1 expression in PDAC cells through NF-κB signaling. The induction of PD-L1 expression was also caused by co-culture with activated macrophages, and the upregulation was inhibited by neutralization with anti-TNF-α antibody after co-culture with activated macrophages. PD-L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD-L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8-positive T-cell infiltration. These findings indicate that tumor-infiltrating macrophage-derived TNF-α could be a potential therapeutic target for PDAC.
Volume 110(1)
Pages 310-320
Published 2019-1-1
DOI 10.1111/cas.13874
PMID 30426611
PMC PMC6317925
MeSH Aged B7-H1 Antigen / genetics* B7-H1 Antigen / metabolism Carcinoma, Pancreatic Ductal / genetics* Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / pathology Cell Line, Tumor Female Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Macrophages / metabolism* Macrophages / pathology Male Middle Aged Pancreatic Neoplasms / genetics* Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology Prognosis Tumor Necrosis Factor-alpha / genetics* Tumor Necrosis Factor-alpha / metabolism
IF 4.751
Times Cited 9
Human and Animal Cells DAUDI(RCB1640)