Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway.
Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway.
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DOI：
10.1126/scitranslmed.3007579
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发表时间：
2014-04-09
影响因子：
17.1
通讯作者：
Hayday A
中科院分区：
文献类型：
--
作者：
Vantourout P;Willcox C;Turner A;Swanson CM;Haque Y;Sobolev O;Grigoriadis A;Tutt A;Hayday A
人类细胞溶解性T淋巴细胞和NK细胞可以限制肿瘤生长，并且越来越多地用于肿瘤免疫治疗。溶细胞淋巴细胞识别肿瘤细胞的一种方式是通过云母/B和ULBP家族的应激抗原与其活化受体NKG 2D接合。这项研究表明，人上皮细胞对紫外线照射、渗透压休克、氧化应激和生长因子供应的NKG 2D配体表面上调可归因于EGF受体（EGFR）的激活。EGFR激活导致AUF 1蛋白的细胞内重新定位，通常通过靶向大多数人NKG 2D配体基因（而非鼠NKG 2D配体基因）3′端内保守的富含AU的元件使NKG 2D配体mRNA不稳定。与这些发现一致，原发性人类癌症的NKG 2D配体表达与EGFR表达呈正相关，EGFR表达通常在此类肿瘤中过度活化，并通过临床EGFR抑制剂降低。因此，应激诱导的EGFR活化不仅调节细胞生长，而且伴随地调节细胞的免疫可见性。因此，设计用于限制癌细胞生长的疗法也应该考虑其对免疫监视的影响。
Human cytolytic T lymphocytes and NK cells can limit tumor growth and are being increasingly harnessed for tumor immunotherapy. One way cytolytic lymphocytes recognize tumor cells is by engagement of their activating receptor, NKG2D, by stress-antigens of the MICA/B and ULBP families. This study shows that surface upregulation of NKG2D ligands by human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor provision, is attributable to activation of the EGF-receptor (EGFR). EGFR activation causes intracellular re-localisation of AUF1 proteins that ordinarily destabilise NKG2D ligand mRNAs by targeting an AU-rich element conserved within the 3′ ends of most human but not murine NKG2D ligand genes. Consistent with these findings, NKG2D ligand expression by primary human carcinomas positively correlated with EGFR expression that is commonly hyper-activated in such tumours, and was reduced by clinical EGFR inhibitors. Thus, stress-induced activation of EGFR not only regulates cell growth but concomitantly regulates the cells’ immunological visibility. Thus, therapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.
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影响因子：
2.8
作者：
Aoki-Yoshida, Ayako;Aoki, Reiji;Takayama, Yoshiharu
通讯作者：
Takayama, Yoshiharu
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.1097/igc.0b013e31825b7dcc
发表时间：
2012-09-01
影响因子：
4.8
作者：
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通讯作者：
Cift, Tayfur
影响因子：
100.3
作者：
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通讯作者：
Trowsdale, John
影响因子：
4
作者：
Furugaki, Koh;Moriya, Yoichiro;Iwai, Toshiki;Yorozu, Keigo;Yanagisawa, Mieko;Kondoh, Kumiko;Fujimoto-Ohuchi, Kaori;Mori, Kazushige
通讯作者：
Mori, Kazushige