CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival.
CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival.
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DOI：
10.1158/0008-5472.can-14-1752
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发表时间：
2015-03
期刊：
影响因子：
11.2
通讯作者：
N. Ullrich;A. Heinemann;Elena Nilewski;I. Scheffrahn;J. Klode;A. Scherag;D. Schadendorf;B. Singer;I. Helfrich
中科院分区：
文献类型：
--
作者：
N. Ullrich;A. Heinemann;Elena Nilewski;I. Scheffrahn;J. Klode;A. Scherag;D. Schadendorf;B. Singer;I. Helfrich
CEACAM 1是一种广泛表达的多功能细胞-细胞粘附蛋白，据报道可作为黑色素瘤患者的不良预后标志物。在这项研究中，我们研究了CEACAM 1的四种剪接异构体的功能和临床贡献。具体来说，我们目前在体外和体内的证据表明，他们影响黑色素瘤的进展和免疫监视的消极或积极的方式是亚型特异性的行动。与同工型CEACAM 1 -4S和CEACAM 1 -4L相反，同工型CEACAM 1 -3S和CEACAM 1 -3L的表达在显示与临床阶段相关的疾病进展期间被诱导。出乎意料的是，表达CEACAM 1 -3S的晚期黑色素瘤患者的总生存期延长。CEACAM 1 -3S的有利作用与增强的免疫原性有关，这是由NKG 2D受体配体的细胞表面上调介导的，从而使黑素瘤细胞对自然杀伤细胞的裂解敏感。相反，CEACAM 1 -4L通过增强脱落下调NKG 2D配体云母和ULBP 2的细胞表面水平，从而促进恶性特征。总的来说，我们的研究结果确定了剪接异构体特异性免疫调节和细胞生物学功能的CEACAM 1在黑色素瘤发病机制。
CEACAM1 is a widely expressed multifunctional cell-cell adhesion protein reported to serve as a poor prognosis marker in melanoma patients. In this study, we examine the functional and clinical contributions of the four splice isoforms of CEACAM1. Specifically, we present in vitro and in vivo evidence that they affect melanoma progression and immune surveillance in a negative or positive manner that is isoform specific in action. In contrast with isoforms CEACAM1-4S and CEACAM1-4L, expression of isoforms CEACAM1-3S and CEACAM1-3L is induced during disease progression shown to correlate with clinical stage. Unexpectedly, overall survival was prolonged in patients with advanced melanomas expressing CEACAM1-3S. The favorable effects of CEACAM1-3S related to enhanced immunogenicity, which was mediated by cell surface upregulation of NKG2D receptor ligands, thereby sensitizing melanoma cells to lysis by natural killer cells. Conversely, CEACAM1-4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character. Overall, our results define the splice isoform-specific immunomodulatory and cell biologic functions of CEACAM1 in melanoma pathogenesis.