JCI：利用免疫系统对抗癌症

人体免疫系统有识别和攻击肿瘤细胞的能力。自然杀伤（NK）细胞是先天免疫细胞，由于其具有分泌细胞毒性酶的能力，能有效地杀死肿瘤细胞。然而，基因突变使许多类型的肿瘤能发展拥有抵抗NK细胞杀伤能力。波士顿达纳法伯癌症研究所的Jerome Ritz博士和他的同事使用短发夹RNA（shRNA）试图找出其中机制。shRNA是short hairpin RNA 的缩写。翻译为“短发夹RNA”。shRNA包括两个短反向重复序列，中间由一茎环（loop）序列分隔的，组成发夹结构，由pol Ⅲ启动子控制。

研究小组使用多发性骨髓瘤细胞株筛选能降低NK细胞对癌细胞敏感性的基因表达情况。他们发现用shRNA干扰关闭某几十个基因时，NK细胞杀伤肿瘤细胞的能力增加了。JAK1和JAK2沉默蛋白激酶许多膜受体蛋白结合信号的重要诱导作用最强。此外，shRNA作用于这些激酶后，研究人员发现抑制JAK1和JAK2的药物增加了NK细胞对肿瘤细胞的杀伤能力。作用于这些基因的许多激酶抑制剂已被上市使用或正在进行临床测试。研究人员建议靶向针对JAK1和JAK2信号途径可能有助于消除肿瘤细胞逃避NK细胞的杀伤机制。

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.