Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer
Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer
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DOI：
10.1158/0008-5472.can-11-0367
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发表时间：
2011-08-15
期刊：
影响因子：
11.2
通讯作者：
Bendriss-Vermare, Nathalie
中科院分区：
文献类型：
--
作者：
Labidi-Galy, Sana Intidhar;Sisirak, Vanja;Bendriss-Vermare, Nathalie
在卵巢癌中，免疫系统无法根除已形成的肿瘤，部分原因是肿瘤微环境中诱导了免疫耐受。在这项研究中，我们研究了浆细胞样树突状细胞（pDC）在44例卵巢癌患者免疫耐受建立中的作用。在肿瘤和恶性腹水中，CD4(+)CD123(+)BDCA2(+) pDC是最丰富的树突状细胞亚群；然而，它们在外周血中被严重耗尽。原发性卵巢癌中pDC的存在，而不是腹水，是与早期复发相关的独立预后因素。化疗后，我们观察到完全缓解的患者血液pDC水平部分恢复。这些发现表明pDC在肿瘤中优先募集，在那里它们表达部分成熟的表型，这可能反映了原位激活。重要的是，与腹水或血液中发现的pDC相比，肿瘤相关pDC （TApDC）在toll样受体刺激下产生的ifn - α、tnf - α、IL-6、巨噬细胞炎症蛋白-1 β和RANTES较少，并且pDC功能的改变主要通过肿瘤源性tnf - α和tgf - β介导。与腹水来源的pDC不同，TApDC诱导同种异体初始CD4(+) T淋巴细胞产生IL-10，表明旁分泌免疫抑制环的存在。综上所述，我们的研究结果表明，pDC的局部和全身功能障碍通过诱导免疫耐受在卵巢癌的进展中发挥关键作用。癌症Res;71 (16);5423 - 34。(c) 2011年AACR。
In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4(+)CD123(+)BDCA2(+) pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-alpha, TNF-alpha, IL-6, macrophage inflammatory protein-1 beta, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-alpha and TGF-beta. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4(+) T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. Cancer Res; 71(16); 5423-34. (c) 2011 AACR.