NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases.
NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases.
复制标题
DOI：
10.1002/ijc.29480
复制
发表时间：
2015-09-01
影响因子：
6.4
通讯作者：
Niederkorn JY
中科院分区：
文献类型：
--
作者：
Sadegh L;Chen PW;Brown JR;Han Z;Niederkorn JY
葡萄膜黑色素瘤（Uveal melanoma， UM）是成人最常见的眼内肿瘤，肝转移是UM患者死亡的主要原因。我们之前的研究表明，与野生型（WT）小鼠相比，NKT细胞缺陷小鼠的眼内黑色素瘤肝转移明显减少。在这里，我们研究了肝脏NKT细胞和NK细胞在抵抗眼内黑色素瘤肝转移中的相互作用。用抗CD1d抗体处理的NKT细胞缺陷CD1d - / -小鼠和WT C57BL/6小鼠在眼内或脾内注射B16LS9黑色素瘤细胞后发生的肝转移明显少于WT小鼠。WT小鼠转移瘤数量的增加与肝脏NK细胞毒性降低和IFN-γ产生减少有关。然而，肝脏NK细胞介导的细胞毒活性在非荷瘤NKT细胞缺陷小鼠和WT小鼠中是相同的，这表明肝转移对肝脏NK细胞的抑制至关重要。WT小鼠肝脏NK细胞毒性降低与骨髓源性肝细胞（既不是Kupffer细胞也不是髓源性抑制细胞）产生IL-10以及肝脏NK细胞上IL-10受体表达增加有关。IL-10−/−小鼠的肝转移明显少于WT小鼠，但与NKT细胞缺陷小鼠无显著差异。因此，黑色素瘤肝转移的发展与肝脏中IL-10的上调和肝脏NK细胞上IL-10受体的表达升高有关。这种肝脏NK细胞活性的损害依赖于NKT细胞，并且仅发生在黑色素瘤肝转移的宿主中。
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.