Immune evasion by murine melanoma mediated through CC chemokine receptor-10.

Immune evasion by murine melanoma mediated through CC chemokine receptor-10.
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DOI:
10.1084/jem.20030593
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发表时间:
2003-11-03
期刊:
The Journal of experimental medicine
影响因子:
--
通讯作者:
Hwang ST
Hwang ST
中科院分区:
其他
文献类型:
--
作者:
Murakami T;Cardones AR;Finkelstein SE;Restifo NP;Klaunberg BA;Nestle FO;Castillo SS;Dennis PA;Hwang ST

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人黑色素瘤细胞经常表达CC趋化因子受体(CCR)10,其配体(CCL 27)由角质形成细胞组成性产生的受体。与B16小鼠黑色素瘤细胞相比,通过过表达荧光素酶使细胞具有更高的免疫原性,过表达荧光素酶和CCR 10的B16细胞抵抗宿主免疫应答,并且容易形成肿瘤。在体外,肿瘤细胞暴露于CCL 27导致Akt的快速激活,对黑色素瘤抗原特异性细胞毒性T细胞诱导的细胞死亡的抵抗,以及磷脂酰肌醇-3-激酶(PI 3 K)依赖性保护免于Fas交联诱导的细胞凋亡。在体内,皮肤注射内源性CCL 27的中和抗体阻断了表达CCR 10的黑色素瘤细胞的生长。我们提出,CCR 10与局部产生的CCL 27的结合允许黑色素瘤细胞逃避宿主免疫抗肿瘤杀伤机制(可能通过激活PI 3 K/Akt),从而为肿瘤进展提供了一种手段。
Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)–dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.
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