Impairment of plasmacytoid dendritic cells for IFN production by the ligand for immunoglobulin-like transcript 7 expressed on human cancer cells.
OBJECTIVE
Plasmacytoid dendritic cells (pDC) are specialized cells to produce type I IFN. Infiltration of pDCs in cancer tissues that have impaired ability to produce IFN-alpha has been suggested to play immunosuppressive roles in tumor immunity. To identify potential mechanisms causing pDC impairment in the cancer microenvironment, expression of immunoglobulin-like transcript 7 ligands (ILT7L), which inhibits pDC production of type I IFNs on the surface of various human cancer and noncancer cells, was examined.


METHODS
To detect unidentified ILT7L, reporter cells, which express green fluorescent protein on interaction with ILT7L, were constructed. ILT7L expression on various human cancer cell lines as well as various noncancerous stromal cells and immune cells was examined. Cytokines and signals involved in the ILT7L expression were also investigated.


RESULTS
ILT7L was detected on all of the various types of human cancer cell lines tested. IFN-alpha, IFN-beta, IFN-gamma, tumor necrosis factor-alpha, interleukin-1beta, transforming growth factor-beta, lipopolysaccharide, and imiquimod induced ILT7L expression on cancer and noncancer cells. High ILT7L-expressing cancer cells inhibited production of IFN-alpha and tumor necrosis factor-alpha by pDC stimulated with CpG. ILT7L does not appear to be a member of classic or nonclassic HLAs. Additionally, NF-kappaB and mammalian target of rapamycin are involved in regulating ILT7L expression.


CONCLUSIONS
ILT7L expression on cancer cells may be one of the mechanisms for impairment of pDCs in the cancer microenvironment. ILT7/ILT7L signaling may normally enable a negative immune response feedback following viral infection. Intervention of the ILT7L/ILT7 system may be useful for enhancing antitumor immunity as well as antiviral immunity.
Tsukamoto
Nobuo
N
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
Okada
Starlyn
S
Onami
Yoko
Y
Sasaki
Yusuke
Y
Umezawa
Kazuo
K
Kawakami
Yutaka
Y
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003512:Cyclohexanones / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008024:Ligands; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D017455:Receptors, IgE / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D001549:Benzamides; C408982:CPG-oligonucleotide; D003512:Cyclohexanones; D016207:Cytokines; C488262:LILRA4 protein, human; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D017455:Receptors, IgE; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C464444:dehydroxymethylepoxyquinomicin; D007371:Interferon-gamma