Gene electrotransfer of proinflammatory chemokines CCL5 and CCL17 as a novel approach of modifying cytokine expression profile in the tumor microenvironment
Gene electrotransfer of proinflammatory chemokines CCL5 and CCL17 as a novel approach of modifying cytokine expression profile in the tumor microenvironment
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DOI：
10.1016/j.bioelechem.2021.107795
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发表时间：
2021-03-28
影响因子：
5
通讯作者：
Markelc, B.
中科院分区：
文献类型：
--
作者：
Bozic, T.;Sersa, G.;Markelc, B.
免疫治疗的有效性与肿瘤组织中免疫细胞浸润的程度和类型高度相关。因此，基于改变肿瘤微环境的免疫细胞浸润的治疗正在获得动力。因此，我们研究的目的是研究两种促炎趋化因子 CCL5 和 CCL17 的基因治疗对两种小鼠乳腺肿瘤模型 4T1 和 E0771 以及两种小鼠结肠肿瘤模型 CT26 和 MC38 中炎症细胞因子表达谱和免疫细胞浸润的影响。在体外，编码 CCL5 或 CCL17 的质粒 DNA 的脂转染导致细胞因子表达谱发生与对照质粒 DNA 类似的变化，这意味着这些变化的主要驱动因素是外源 DNA 进入细胞的细胞质。在体内，基因电转移导致 4T1 和 CT26 肿瘤模型中 Ccl5 和 Ccl17 转基因高表达。除了治疗小鼠的存活率略有增加外，该疗法还导致 CT26 肿瘤中 Cxcl9 和 Ifnc（免疫系统的有效激活剂）表达增加。然而，这并没有在 TME 的变化中得到体现，这意味着需要进一步完善给药方案。 (C) 2021 作者。由 Elsevier B.V. 出版
The effectiveness of immunotherapy highly correlates with the degree and the type of infiltrated immune cells in the tumor tissue. Treatments based on modifying the immune cell infiltrate of the tumor microenvironment are thus gaining momentum. Therefore, the aim of our study was to investigate the effects of gene therapy with two proinflammatory chemokines CCL5 and CCL17 on inflammatory cytokine expression profile and immune cell infiltrate in two murine breast tumor models, 4T1 and E0771, and two murine colon tumor models, CT26 and MC38. In vitro, lipofection of plasmid DNA encoding CCL5 or CCL17 resulted in changes in the cytokine expression profile similar to control plasmid DNA, implying that the main driver of these changes was the entry of foreign DNA into the cell's cytosol. In vivo, gene electrotransfer resulted in high expression levels of both Ccl5 and Ccl17 transgenes in the 4T1 and CT26 tumor models. Besides a minor increase in the survival of the treated mice, the therapy also resulted in increased expression of Cxcl9 and Ifnc, potent activators of the immune system, in CT26 tumors. However, this was not recapitulated in changes of TME, implying that a further refinement of the dosing schedule is needed. (C) 2021 The Authors. Published by Elsevier B.V.