title: NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases.
abstract: Uveal melanoma (UM) is the most common intraocular tumor in adults and liver metastasis is the leading cause of death in UM patients. We have previously shown that NKT cell-deficient mice develop significantly fewer liver metastases from intraocular melanomas than do wild-type (WT) mice. Here, we examine the interplay between liver NKT cells and NK cells in resistance to liver metastases from intraocular melanomas. NKT cell-deficient CD1d(-/-) mice and WT C57BL/6 mice treated with anti-CD1d antibody developed significantly fewer liver metastases than WT mice following either intraocular or intrasplenic injection of B16LS9 melanoma cells. The increased number of metastases in WT mice was associated with reduced liver NK cytotoxicity and decreased production of IFN-γ. However, liver NK cell-mediated cytotoxic activity was identical in non-tumor bearing NKT cell-deficient mice and WT mice, indicating that liver metastases were crucial for the suppression of liver NK cells. Depressed liver NK cytotoxicity in WT mice was associated with production of IL-10 by bone marrow-derived liver cells that were neither Kupffer cells nor myeloid-derived suppressor cells and by increased IL-10 receptor expression on liver NK cells. IL-10(-/-) mice had significantly fewer liver metastases than WT mice, but were not significantly different from NKT cell-deficient mice. Thus, development of melanoma liver metastases is associated with upregulation of IL-10 in the liver and an elevated expression of IL-10 receptor on liver NK cells. This impairment of liver NK activity is NKT cell-dependent and only occurs in hosts with melanoma liver metastases.
authors: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Leila
authors: L
authors: Sadegh
authors: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Peter W
authors: PW
authors: Chen
authors: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Joseph R
authors: JR
authors: Brown
authors: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Zhiqiang
authors: Z
authors: Han
authors: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Jerry Y
authors: JY
authors: Niederkorn
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000502:physiology*; D009368:Neoplasm Transplantation; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D014604:Uveal Neoplasms / Q000276:immunology* / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: D000906:Antibodies; D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; C556062:IL10 protein, mouse; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: IL-10; NKG2D; eye; metastases; ocular tumors; uveal melanoma