Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor
Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor
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DOI：
10.1007/s00262-012-1212-x
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发表时间：
2012-09-01
影响因子：
5.8
通讯作者：
Wels, Winfried S.
中科院分区：
文献类型：
--
作者：
Sahm, Christiane;Schoenfeld, Kurt;Wels, Winfried S.
自然杀伤(NK)细胞有望用于癌症的过继免疫治疗，但它的生长和细胞毒性依赖于白细胞介素2(IL-2)等细胞因子。在这里，我们研究了IL-15在人NK细胞中异位表达的后果。IL-2和IL-15属于常见的细胞因子伽马链家族，具有重叠的活性。用编码人IL-15的慢病毒载体转导临床适用的NK-92细胞，在没有IL-2的情况下，主要在细胞内表达细胞因子，并激活、增殖和杀伤产生细胞的STAT5。不支持非转导旁观者细胞的生长，允许仅通过退出IL-2来快速丰富基因修饰的细胞。用编码IL-15的双顺反子慢病毒载体和针对肿瘤抗原EpCAM的嵌合抗原受体(CAR)转导NK-92和NKL细胞时也是如此。共表达CAR和IL-15的效应细胞在没有外源性细胞因子的情况下继续增殖，并对表达EpCAM的乳腺癌细胞显示出高选择性的杀伤活性，这些细胞对未修饰的NK细胞的自然杀伤作用具有抵抗力。这一策略有助于快速分离和持续扩增重定向的NK细胞，并可能扩大其潜在的临床应用价值。
Natural killer (NK) cells hold promise for adoptive cancer immunotherapy but are dependent on cytokines such as interleukin (IL)-2 for growth and cytotoxicity. Here, we investigated the consequences of ectopic expression of IL-15 in human NK cells. IL-2 and IL-15 belong to the common gamma chain family of cytokines and have overlapping activities. Transduction of clinically applicable NK-92 cells with lentiviral vectors encoding human IL-15 resulted in predominantly intracellular expression of the cytokine, and STAT5 activation, proliferation and cytotoxicity of the producer cells in the absence of IL-2. Growth of non-transduced bystander cells was not supported, allowing rapid enrichment of gene-modified cells solely by IL-2 withdrawal. This was also the case upon transduction of NK-92 and NKL cells with a bicistronic lentiviral vector encoding IL-15 and a chimeric antigen receptor (CAR) targeting the pancarcinoma antigen EpCAM. Effector cells co-expressing CAR and IL-15 continued to proliferate in the absence of exogenous cytokines and displayed high and selective cell-killing activity against EpCAM-expressing breast carcinoma cells that were resistant to the natural cytotoxicity of unmodified NK cells. This strategy facilitates rapid isolation and continuous expansion of retargeted NK cells and may extend their potential clinical utility.