Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer.
Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer.
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DOI：
10.4049/jimmunol.182.3.1746
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发表时间：
2009-02-01
期刊：
影响因子：
--
通讯作者：
Linehan DC
中科院分区：
文献类型：
--
作者：
Tan MC;Goedegebuure PS;Belt BA;Flaherty B;Sankpal N;Gillanders WE;Eberlein TJ;Hsieh CS;Linehan DC
肿瘤通过募集CD 4 + CD 25 + Foxp 3+调节性T细胞（Treg）主动诱导免疫耐受来逃避免疫破坏。我们之前已经描述了这些细胞在胰腺癌中的患病率增加，但仍不清楚是什么机制参与了将Treg招募到肿瘤微环境中。在此，我们假设趋化因子可能指导Treg归巢至肿瘤。我们发现，在人胰腺癌和小鼠胰腺肿瘤模型（Pan 02）中，肿瘤细胞产生的CCR 5趋化因子受体配体水平增加，而且，与CD 4 + Foxp 3 −效应T细胞相比，CD 4 + Foxp 3 + Treg优先表达CCR 5。当CCR 5/CCL 5信号传导被破坏时，通过减少肿瘤细胞的CCL 5产生或通过全身给予CCR 5抑制剂（TAK-779），Treg向肿瘤的迁移减少，肿瘤比对照小鼠小。因此，这项研究证明了Treg在肿瘤免疫逃避中的重要性，Treg迁移的阻断如何抑制肿瘤生长，特别是在胰腺癌中，CCR 5在肿瘤相关Treg归巢中的作用。选择性靶向CCR 5/CCL 5信号传导可能代表了用于治疗癌症的新型免疫调节策略。
Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4+CD25+Foxp3+ regulatory T cells (Treg). We have previously described increased prevalence of these cells in pancreatic adenocarcinoma, but it remains unclear what mechanisms are involved in recruiting Treg into the tumor microenvironment. Here, we postulated that chemokines might direct Treg homing to tumor. We show, in both human pancreatic adenocarcinoma and a murine pancreatic tumor model (Pan02), that tumor cells produce increased levels of ligands for the CCR5 chemokine receptor, and, reciprocally, that CD4+ Foxp3+ Treg, compared with CD4+ Foxp3− effector T cells, preferentially express CCR5. When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Treg in immune evasion by tumors, how blockade of Treg migration may inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Treg. Selective targeting of CCR5/CCL5 signaling may represent a novel immunomodulatory strategy for the treatment of cancer.
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影响因子：
4.9
作者：
Hasegawa H;Inoue A;Muraoka M;Yamanouchi J;Miyazaki T;Yasukawa M
通讯作者：
Yasukawa M
影响因子：
11.5
作者：
Kline, Justin;Brown, Ian E.;Gajewski, Thomas F.
通讯作者：
Gajewski, Thomas F.
影响因子：
6.4
作者：
Grauer, Oliver M.;Nierkens, Stefan;Adema, Gosse J.
通讯作者：
Adema, Gosse J.
影响因子：
64.8
作者：
Karnoub, Antoine E.;Dash, Ajeeta B.;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.
DOI：
10.1073/pnas.96.10.5698
发表时间：
1999-05-11
影响因子：
11.1
作者：
Baba, M;Nishimura, O;Fujino, M
通讯作者：
Fujino, M