A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.
A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.
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一种新型的三维异型球体模型，用于评估癌症免疫疗法的活性。
DOI：
10.1007/s00262-016-1927-1
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Bacac M
中科院分区：
文献类型：
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作者：
Herter S;Morra L;Schlenker R;Sulcova J;Fahrni L;Waldhauer I;Lehmann S;Reisländer T;Agarkova I;Kelm JM;Klein C;Umana P;Bacac M
肿瘤微环境的复杂性很难在体外模拟，特别是关于肿瘤-宿主相互作用。为了能够更好地评估体外癌症免疫治疗剂，我们开发了一种由肿瘤细胞、成纤维细胞和免疫细胞组成的三维（3D）异型球体模型。药物靶向，有效刺激免疫细胞浸润，和肿瘤或成纤维细胞球体区域的特异性消除后，证明了一种新的免疫细胞因子（白细胞介素-2变异体; IgG-IL 2 v）和肿瘤或成纤维细胞靶向T细胞双特异性抗体（TCB）治疗。在用IgG-IL 2 v处理后，通过活化标志物CD 69的表达增加和细胞因子分泌增强来证明T细胞、NK细胞和NKT细胞的活化。TCB与IgG-IL 2 v分子的组合比单一疗法更有效，如对免疫细胞浸润的增强作用;活化;增加的细胞因子分泌;以及更快、更有效地消除靶细胞所示。这项研究表明，3D异型球体模型为癌症免疫治疗剂的体外评价提供了一种新颖而通用的工具，并允许评估癌症免疫治疗剂活性的其他方面，包括免疫细胞浸润和药物靶向分析。本文的在线版本（doi：10.1007/s 00262 -016-1927-1）包含补充材料，可供授权用户使用。
The complexity of the tumor microenvironment is difficult to mimic in vitro, particularly regarding tumor–host interactions. To enable better assessment of cancer immunotherapy agents in vitro, we developed a three-dimensional (3D) heterotypic spheroid model composed of tumor cells, fibroblasts, and immune cells. Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB). Following treatment with IgG-IL2v, activation of T cells, NK cells, and NKT cells was demonstrated by increased expression of the activation marker CD69 and enhanced cytokine secretion. The combination of TCBs with IgG-IL2v molecules was more effective than monotherapy, as shown by enhanced effects on immune cell infiltration; activation; increased cytokine secretion; and faster, more efficient elimination of targeted cells. This study demonstrates that the 3D heterotypic spheroid model provides a novel and versatile tool for in vitro evaluation of cancer immunotherapy agents and allows for assessment of additional aspects of the activity of cancer immunotherapy agents, including analysis of immune cell infiltration and drug targeting. The online version of this article (doi:10.1007/s00262-016-1927-1) contains supplementary material, which is available to authorized users.