Open AccessPD ‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis
Author(s) -
Tsukamoto Masayo,
Imai Katsunori,
Ishimoto Takatsugu,
Komohara Yoshihiro,
Yamashita Yoichi,
Nakagawa Shigeki,
Umezaki Naoki,
Yamao Takanobu,
Kitano Yuki,
Miyata Tatsunori,
Arima Kota,
Okabe Hirohisa,
Baba Yoshifumi,
Chikamoto Akira,
Ishiko Takatoshi,
Hirota Masahiko,
Baba Hideo
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13874
Subject(s) - tumor necrosis factor alpha , cancer research , downregulation and upregulation , pancreatic cancer , immunotherapy , infiltration (hvac) , macrophage , stroma , pd l1 , tumor infiltrating lymphocytes , medicine , antibody , cancer , immune system , biology , immunology , immunohistochemistry , gene , in vitro , biochemistry , physics , thermodynamics
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 CD 8‐positive T‐cell infiltration. These findings indicate that tumor‐infiltrating macrophage‐derived TNF ‐α could be a potential therapeutic target for PDAC .