Premium
Gene transfer of the CD40‐ligand to human dendritic cells induces NK‐mediated antitumor effects against human carcinoma cells
Author(s) -
Tomihara Kei,
Kato Kazunori,
Masuta Yukari,
Nakamura Kiminori,
Tanaka Toshihiro,
Hiratsuka Hiroyoshi,
Hamada Hirofumi
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22518
Subject(s) - cd40 , cytotoxic t cell , interleukin 12 , perforin , microbiology and biotechnology , biology , granzyme b , immune system , dendritic cell , granzyme , interleukin 21 , chemistry , t cell , immunology , cd8 , in vitro , biochemistry
The CD40‐ligand (CD40L) is a key molecule for the activation of dendritic cells (DCs), followed by the induction of DC maturation and cytokine production. Here we found that DC infected with adenovirus vector encoding human CD40L (CD40L‐DC) displayed significantly higher levels of immune accessory molecules and IL‐12 production than did uninfected cells, and that CD40L‐DC produced much higher levels of IFN‐γ. To investigate whether CD40L‐DC‐derived these soluble factors could stimulate NK cells without physical cell‐to‐cell contact, we cocultured NK cells with CD40L‐DC in transwell culture plates. NK cells showed up‐regulated cytotoxic activity toward various squamous oral cell carcinoma (OSC‐70, HSC‐2, HSC‐3), and we determined that both IL‐12 and IFN‐γ contributed to the CD40L‐DC‐mediated NK cell activation. NK cells stimulated with CD40L‐DC resulted in the induction of the cell surface expression of TRAIL, the production of IFN‐γ and intracellular accumulation of granzyme B. The cytotoxic activity of NK cells stimulated with CD40L‐DC could be mostly inhibited by neutralizing antibody for TRAIL and completely abrogated by the combination of antibody and exocytosis inhibitor, indicating that this was mainly mediated by a TRAIL‐TRAIL‐receptor interaction and granule exocytosis. Moreover, CD40L‐DC‐activated NK cells could induce up‐regulation of a death‐receptor TRAIL‐R2 (DR5) and down‐regulation of a decoy receptor TRAIL‐R3 (DcR1) on carcinoma cells. Overall, these results have revealed that CD40L‐DC could activate an innate immune reaction by stimulating NK cells followed by carcinoma cells, supporting that administration of CD40L‐DC may have potential as an anticancer therapy. © 2006 Wiley‐Liss, Inc.