Division of Medical Oncology, Experimental Cell Therapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Mol Med. 2017 Oct;23:235-246. doi: 10.2119/molmed.2017.00084. Epub 2017 Aug 9.
Adoptive immunotherapy with Cytokine Induced Killer (CIK) cells has shown antitumor activity against several kinds of cancers in preclinical models and clinical trials. CIK cells are a subset of ex vivo expanded T lymphocytes with T-NK phenotype and MHC-unrestricted antitumor activity. Literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. Therefore, we investigated the secretory profile of CIK cells generated from tumor patients. The secretome analysis was performed at specific time points (day 1, day 14 and day 21) of CIK cells expansion. Mature CIK cells (day 21) produce a great variety of interleukins and secreted proteins that can be divided into 3 groups based on their secretion quantity: high (IL-13, RANTES, MIP-1α and 1β), medium (IL-1Ra, IL-5, IL-8, IL-10, IL-17, IP-10, INF-γ, VEGF and GMCSF) and low (IL-1β, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, Eotaxin, PDGF-bb, FGF basic, G-CSF and MCP-1) secreted. Moreover, comparing PBMC (day 1) and mature CIK cells (day 14 and 21) secretome, we observed that IL-5, IL-10, IL-13, GM-CSF, VEGF resulted greatly up-regulated, while IL-1β, IL-6, IL-8, IL-15, IL-17, eotaxin, MCP-1, and RANTES were down-regulated. We also performed a gene expression profile analysis of patient-derived CIK cells showing that mRNA for the different cytokines and secreted proteins were modulated during PBMC to CIK differentiation. We highlighted previously unknown secretory properties and provided for the first time a comprehensive molecular characterization of CIK cells. Our findings provide rationale to explore the functional implications and possible therapeutic modulation of CIK secretome.
过继免疫疗法用细胞因子诱导的杀伤（CIK）细胞已显示出在临床前模型和临床试验中对多种癌症的抗肿瘤活性。CIK 细胞是体外扩增的 T 淋巴细胞的一个亚群，具有 T-NK 表型和 MHC 非限制性抗肿瘤活性。文献中关于 CIK 细胞分泌的细胞因子、趋化因子和生长因子的信息很少。因此，我们研究了来自肿瘤患者的 CIK 细胞的分泌谱。在 CIK 细胞扩增的特定时间点（第 1 天、第 14 天和第 21 天）进行了分泌组分析。成熟的 CIK 细胞（第 21 天）产生大量的白细胞介素和分泌蛋白，根据其分泌量可分为 3 组：高（IL-13、RANTES、MIP-1α 和 1β）、中（IL-1Ra、IL-5、IL-8、IL-10、IL-17、IP-10、INF-γ、VEGF 和 GMCSF）和低（IL-1β、IL-4、IL-6、IL-7、IL-9、IL-12、IL-15、Eotaxin、PDGF-bb、FGF 碱性、G-CSF 和 MCP-1）。此外，比较 PBMC（第 1 天）和成熟的 CIK 细胞（第 14 天和第 21 天）的分泌组，我们观察到 IL-5、IL-10、IL-13、GM-CSF 和 VEGF 显著上调，而 IL-1β、IL-6、IL-8、IL-15、IL-17、Eotaxin、MCP-1 和 RANTES 下调。我们还对患者来源的 CIK 细胞进行了基因表达谱分析，结果表明不同细胞因子和分泌蛋白的 mRNA 在 PBMC 向 CIK 分化过程中发生了调节。我们强调了以前未知的分泌特性，并首次对 CIK 细胞进行了全面的分子特征描述。我们的研究结果为探索 CIK 分泌组的功能意义和可能的治疗调节提供了依据。
