A dynamic transcriptomic atlas of cytokine-induced killer cells.
A dynamic transcriptomic atlas of cytokine-induced killer cells.
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细胞因子诱导的杀伤细胞的动态转录组图谱。
DOI：
10.1074/jbc.ra118.003280
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发表时间：
2018-12-21
期刊：
影响因子：
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通讯作者：
Hou Z
中科院分区：
文献类型：
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作者：
Meng M;Li L;Li R;Wang W;Chen Y;Xie Y;Han R;Zhu K;Huang W;Yang L;Li S;Shi J;Tan W;Gao H;Zhao Y;Yang L;Tan J;Hou Z
已经报道了几个使用尼古丁诱导的杀伤（CIK）细胞的临床免疫治疗试验。然而，在将其投入临床使用之前，需要细胞扩增、获得肿瘤细胞毒性和CIK细胞安全性的分子证据。在此，我们对暴露于干扰素-γ、OKT 3和白细胞介素-2的原代外周血单核细胞产生的CIK进行了动态转录组学分析。在第0、1、7和14天提取CIK mRNA并测序，并进行生物信息学分析。使用加权相关网络分析（WGCNA），我们确定了两个主要的基因模块，介导免疫细胞活化和有丝分裂。我们发现CIK细胞的活化和细胞毒性可能依赖于分化簇8（CD 8）及其蛋白伴侣LCK原癌基因Src家族酪氨酸激酶（LCK）。时程系列分析显示，由于某些自身抗原的表达减少，CIK细胞的免疫原性相对较低。重要的是，我们确定了几个关键的活化受体和辅助粘附受体表达的CIK细胞，可能作为肿瘤传感器。有趣的是，细胞毒性相关基因，包括那些编码PRF 1，GZMB，FASL，和几种细胞因子，在成熟的CIK细胞上调。大多数免疫检查点分子和炎性肿瘤促进因子在CIK细胞中下调，表明在未来的临床试验中有效性和安全性。值得注意的是，胰岛素样生长因子1（IGF-1）在CIK细胞中高度表达，并可能促进细胞毒性，尽管它也可能促进肿瘤发生。CIK细胞的转录组图谱可以为临床试验中改善CIK相关肿瘤细胞毒性和安全性的努力提供信息。
Several clinical immunotherapy trials with cytokine-induced killer (CIK) cells have been reported. However, molecular evidence of cell expansion, acquisition of tumor cytotoxicity, and safety of CIK cells is required before putting them to clinical use. Here, we performed dynamic transcriptomic analyses of CIKs generated from primary peripheral blood mononuclear cells exposed to interferon-γ, OKT3, and interleukin-2. CIK mRNAs were extracted and sequenced at days 0, 1, 7, and 14 and subjected to bioinformatics analyses. Using weighted correlation network analysis (WGCNA), we identified two major gene modules that mediate immune cell activation and mitosis. We found that activation and cytotoxicity of CIK cells likely rely on cluster of differentiation 8 (CD8) and its protein partner LCK proto-oncogene, Src family tyrosine kinase (LCK). A time-course series analysis revealed that CIK cells have relatively low immunogenicity because of decreased expression of some self-antigens. Importantly, we identified several crucial activating receptors and auxiliary adhesion receptors expressed on CIK cells that may function as tumor sensors. Interestingly, cytotoxicity-associated genes, including those encoding PRF1, GZMB, FASL, and several cytokines, were up-regulated in mature CIK cells. Most immune-checkpoint molecules and inflammatory tumor-promoting factors were down-regulated in the CIK cells, suggesting efficacy and safety in future clinical trials. Notably, insulin-like growth factor 1 (IGF-1) was highly expressed in CIK cells and may promote cytotoxicity, although it also could facilitate tumorigenesis. The transcriptomic atlas of CIK cells presented here may inform efforts to improve CIK-associated tumor cytotoxicity and safety in clinical trials.