HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.
HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.
复制标题
DOI：
10.1084/jem.20100587
复制
发表时间：
2010-10-25
期刊：
影响因子：
--
通讯作者：
Gabrilovich DI
中科院分区：
文献类型：
--
作者：
Corzo CA;Condamine T;Lu L;Cotter MJ;Youn JI;Cheng P;Cho HI;Celis E;Quiceno DG;Padhya T;McCaffrey TV;McCaffrey JC;Gabrilovich DI
肿瘤的缺氧环境通过HIF-1a表达决定了局部髓源性抑制细胞（MDSCs）的表型；缺氧将脾MDSCs从特异性抑制转化为非特异性抑制。髓源性抑制细胞（MDSCs）是癌症和许多其他病理条件中描述的免疫抑制网络的主要组成部分。我们证明，尽管来自外周淋巴器官和肿瘤部位的MDSCs具有相似的表型和形态，但这些细胞表现出深刻的功能差异。来自外周淋巴器官的MDSC抑制抗原特异性CD8+ T细胞，但不能抑制非特异性T细胞功能。与之形成鲜明对比的是，肿瘤MDSC同时抑制抗原特异性和非特异性T细胞活性。肿瘤微环境导致MDSC中精氨酸酶I和诱导型一氧化氮合酶的快速显著上调，同时伴有烟酰胺腺嘌呤二核苷酸磷酸氧化酶和活性氧的下调。与来自脾脏的MDSC相比，来自肿瘤部位的MDSC迅速分化为巨噬细胞。暴露于缺氧的脾脏MDSC导致这些细胞转化为非特异性抑制细胞，并优先分化为巨噬细胞。缺氧诱导因子（HIF） 1α被发现是肿瘤微环境对MDSC分化和功能影响的主要原因。因此，缺氧通过HIF-1α显著改变MDSC在肿瘤微环境中的功能，并将其向肿瘤相关巨噬细胞的分化重新定向，从而提供了肿瘤微环境中不同骨髓抑制细胞之间的机制联系。
The hypoxic environment of tumors dictates the phenotype of local myeloid-derived suppressor cells (MDSCs) via HIF-1a expression; hypoxia converts splenic MDSCs from specific into nonspecific suppressors. Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8+ T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate–oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment.
登录
查看更多内容
影响因子：
4.3
作者：
Lopez, CB;Rao, TD;Frey, AB
通讯作者：
Frey, AB
影响因子：
82.9
作者：
Nagaraj, Srinivas;Gupta, Kapil;Gabrilovich, Dmitry I.
通讯作者：
Gabrilovich, Dmitry I.
影响因子：
4.4
作者：
Nefedova, Y;Huang, M;Gabrilovich, D
通讯作者：
Gabrilovich, D
影响因子：
4.4
作者：
Almand, B;Clark, JI;Gabrilovich, DI
通讯作者：
Gabrilovich, DI
影响因子：
11.2
作者：
Movahedi, Kiavash;Laoui, Damya;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.