Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells
Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells
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DOI：
10.1093/jnci/djv209
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发表时间：
2015-10-01
影响因子：
10.3
通讯作者：
Genove, Guillem
中科院分区：
文献类型：
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作者：
Hong, JongWook;Tobin, Nicholas P.;Genove, Guillem
背景：周细胞是肿瘤基质的成员；然而，对它们的起源、功能或与其他肿瘤成分的相互作用知之甚少。新出现的证据表明周细胞可能调节白细胞的迁移。髓源性抑制细胞（myeloid -derived suppressor cells， MDSC）是一种未成熟的髓细胞，对t细胞介导的抗肿瘤活性具有强大的抑制作用。方法：我们在周细胞缺乏的遗传小鼠模型（pdgfb（ret/ret）小鼠）和同窝对照小鼠（n = 6-25）中产生皮下肿瘤。采用基于双侧Wald检验的Cox比例风险比（hr）和95%置信区间（CIs），对253例乳腺癌患者（I-III期）的基因表达谱进行临床病理参数和生存率评估。结果：我们报道了周细胞缺乏导致Gr1(+)/CD11b（+）细胞在实验诱导肿瘤中的迁移增加。周细胞缺乏导致肿瘤血管缺陷，导致更缺氧的微环境促进恶性细胞中IL-6的上调。沉默肿瘤细胞中IL-6的表达减弱了观察到的MDSC迁移差异。恢复肿瘤的周细胞覆盖消除了增加的MDSC向周细胞缺陷肿瘤的贩运。MDSC在肿瘤中的积累导致肿瘤生长和循环恶性细胞的增加。最后，对人乳腺癌患者的基因表达分析显示，人MDSC标志物CD33和S100A9表达增加，同时周细胞基因表达减少，与预后不良相关（HR = 1.88, 95% CI = 1.08 ~ 3.25, P = 0.03）。结论：我们的数据揭示了肿瘤周细胞和炎症细胞之间的一种新的旁分泌相互作用，并描述了导致MDSC向肿瘤募集的细胞事件。此外，我们首次提出肿瘤周细胞通过促进缺氧微环境来调节恶性细胞中免疫介质的表达。
Background: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity.Methods: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb(ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test.Results: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03).Conclusions: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.