Purpose: 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-α 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.

Experimental Design: 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-α, IFN-β, IFN-γ, tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, lipopolysaccharide, and imiquimod induced ILT7L expression on cancer and noncancer cells. High ILT7L-expressing cancer cells inhibited production of IFN-α and tumor necrosis factor-α by pDC stimulated with CpG. ILT7L does not appear to be a member of classic or nonclassic HLAs. Additionally, NF-κB 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. (Clin Cancer Res 2009;15(18):5733–43)