Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor
Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor
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DOI：
10.1189/jlb.0909607
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发表时间：
2010-04-01
影响因子：
5.5
通讯作者：
Miller, George
中科院分区：
文献类型：
--
作者：
Connolly, Michael K.;Mallen-St Clair, Jon;Miller, George
肝脏是腺癌转移的最常见部位，即使在最初表现为早期疾病的患者中也是如此。我们推测，荷瘤宿主肝脏中的免疫抑制细胞抑制抗肿瘤T细胞，从而加速肝转移瘤的生长。本研究的目的是利用早期胰腺癌和晚期结直肠癌的模型，确定免疫表型、免疫抑制细胞在荷瘤宿主肝脏中的募集刺激、抑制作用和致瘤功能。我们发现，在患有腹腔恶性肿瘤的小鼠中，具有不同表型和功能特性的两种不同的CD 11b（+）Gr 1（+）群体在肝脏中积累，成为主要的肝脏白细胞。它们的扩张取决于KC的肿瘤表达。这些细胞在细胞表型、细胞因子和趋化因子谱方面不同于荷瘤宿主其他组织中的CD 11b（+）Gr 1（+）群体。肝脏CD 11b（+）Gr 1（+）细胞对T细胞活化、增殖和细胞毒性具有高度抑制作用，并诱导T细胞增殖。此外，肝脏骨髓来源的抑制细胞通过灭活细胞毒性T细胞加速肝转移的发展。这些发现可以解释腹腔内癌症患者发生肝转移的倾向，并为实验治疗提供了一个有希望的靶点。J. Leukoc. 87：713-725; 2010.
The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b(+) Gr1(+) populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b(+) Gr1(+) populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b(+) Gr1(+) cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics. J. Leukoc. Biol. 87: 713-725; 2010.