The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion
The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion
复制标题
DOI：
10.1158/2326-6066.cir-14-0199
复制
发表时间：
2015-08-01
影响因子：
10.1
通讯作者：
Haga, Hironori
中科院分区：
文献类型：
--
作者：
Ueshima, Chiyuki;Kataoka, Tatsuki R.;Haga, Hironori
免疫细胞Ig样受体（KIR）2DL 4（CD 158 d）作为人类白细胞抗原（HLA）-G的受体，并且在几乎所有人类自然杀伤（NK）细胞上表达。KIR 2DL 4在其他造血细胞中的表达和功能知之甚少。在这里，我们专注于人类肥大细胞，其表现出类似于NK细胞的细胞毒活性。KIR 2DL 4在从健康志愿者外周血建立的所有检查的人培养肥大细胞（PB-肥大）、人肥大细胞系LAD 2和人非肿瘤性肥大细胞（包括病理标本上的肥大细胞）中检测到。针对KIR 2DL 4的激动性抗体通过激活含Src同源性2的蛋白酪氨酸磷酸酶（SHP-2）来降低KIT介导的和IgE触发的应答，并增强PB-肥大细胞和LAD 2细胞的颗粒酶B产生。接下来，我们进行了LAD 2细胞与HLA-G（+）癌细胞MCF-7和JEG-3之间的共培养测定，并显示LAD 2细胞上的KIR 2DL 4增强MMP-9的产生和两种细胞系通过HLA-G的侵袭活性。免疫组化分析显示HLA-G（+）乳腺癌细胞和KIR 2DL 4（+）组织肥大细胞之间的直接相互作用（12/36例，33.3%）与淋巴结转移或淋巴管浸润相关（12例中11例观察到; 91.7%;卡方（2）= 7.439; P < 0.01;自由度，1）。这些发现表明，人肥大细胞上的KIR 2DL 4促进表达HLA-G的癌症侵袭和随后的转移。
The killer-cell Ig-like receptor (KIR) 2DL4 (CD158d) acts as a receptor for human leukocyte antigen (HLA)-G and is expressed on almost all human natural killer (NK) cells. The expression and function of KIR2DL4 in other hematopoietic cells is poorly understood. Here, we focused on human mast cells, which exhibit cytotoxic activity similar to that of NK cells. KIR2DL4 was detected in all examined human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), the human mast cell line LAD2, and human nonneoplastic mast cells, including those on pathologic specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production by PB-mast and LAD2 cells, by activating Src homology 2-containing protein tyrosine phosphatase (SHP-2). Next, we performed a coculture assay between LAD2 cells and the HLA-G(+) cancer cells, MCF-7 and JEG-3, and showed that KIR2DL4 on LAD2 cells enhanced MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G(+) breast cancer cells and KIR2DL4(+) tissue mast cells (observed in 12 of 36 cases; 33.3%) was statistically correlated with the presence of lymph node metastasis or lymph-vascular invasion (observed in 11 of 12 cases; 91.7%; chi(2) = 7.439; P < 0.01; degrees of freedom, 1) in the clinical samples. These findings suggest that the KIR2DL4 on human mast cells facilitates HLA-G-expressing cancer invasion and the subsequent metastasis.