人體免疫系統(tǒng)有識(shí)別和攻擊腫瘤細(xì)胞的能力,。自然殺傷（NK）細(xì)胞是先天免疫細(xì)胞，由于其具有分泌細(xì)胞毒性酶的能力,，能有效地殺死腫瘤細(xì)胞,。然而，基因突變使許多類型的腫瘤能發(fā)展擁有抵抗NK細(xì)胞殺傷能力,。波士頓達(dá)納法伯癌癥研究所的Jerome Ritz博士和他的同事使用短發(fā)夾RNA（shRNA）試圖找出其中機(jī)制,。shRNA是short hairpin RNA 的縮寫(xiě)。翻譯為“短發(fā)夾RNA”,。shRNA包括兩個(gè)短反向重復(fù)序列，中間由一莖環(huán)（loop）序列分隔的,，組成發(fā)夾結(jié)構(gòu),，由pol Ⅲ啟動(dòng)子控制。
研究小組使用多發(fā)性骨髓瘤細(xì)胞株篩選能降低NK細(xì)胞對(duì)癌細(xì)胞敏感性的基因表達(dá)情況,。他們發(fā)現(xiàn)用shRNA干擾關(guān)閉某幾十個(gè)基因時(shí),，NK細(xì)胞殺傷腫瘤細(xì)胞的能力增加了。JAK1和JAK2沉默蛋白激酶許多膜受體蛋白結(jié)合信號(hào)的重要誘導(dǎo)作用最強(qiáng),。此外,，shRNA作用于這些激酶后，研究人員發(fā)現(xiàn)抑制JAK1和JAK2的藥物增加了NK細(xì)胞對(duì)腫瘤細(xì)胞的殺傷能力,。作用于這些基因的許多激酶抑制劑已被上市使用或正在進(jìn)行臨床測(cè)試,。研究人員建議靶向針對(duì)JAK1和JAK2信號(hào)途徑可能有助于消除腫瘤細(xì)胞逃避NK細(xì)胞的殺傷機(jī)制。（生物谷：Bioon.com）
doi:10.1172/JCI58457
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Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells
Roberto Bellucci, Hong-Nam Nguyen, Allison Martin, Stefan Heinrichs, Anna C. Schinzel, William C. Hahn and Jerome Ritz
Natural killer (NK) cells are primary effectors of innate immunity directed against transformed tumor cells. In response, tumor cells have developed mechanisms to evade NK cell–mediated lysis through molecular mechanisms that are not well understood. In the present study, we used a lentiviral shRNA library targeting more than 1,000 human genes to identify 83 genes that promote target cell resistance to human NK cell–mediated killing. Many of the genes identified in this genetic screen belong to common signaling pathways; however, none of them have previously been known to modulate susceptibility of human tumor cells to immunologic destruction. Gene silencing of two members of the JAK family (JAK1 and JAK2) increased the susceptibility of a variety of tumor cell types to NK-mediated lysis and induced increased secretion of IFN-γ by NK cells. Treatment of tumor cells with JAK inhibitors also increased susceptibility to NK cell activity. These findings may have important clinical implications and suggest that small molecule inhibitors of tyrosine kinases being developed as therapeutic antitumor agents may also have significant immunologic effects in vivo.
