在三维多细胞球体模型中模拟成纤维细胞的免疫抑制作用

Melanie Grotz, Lieke van Gijzel, Peter Bitsch, Stefania C. Carrara, Harald Kolmar, Sakshi Garg
{"title":"在三维多细胞球体模型中模拟成纤维细胞的免疫抑制作用","authors":"Melanie Grotz, Lieke van Gijzel, Peter Bitsch, Stefania C. Carrara, Harald Kolmar, Sakshi Garg","doi":"10.3389/fddsv.2024.1427407","DOIUrl":null,"url":null,"abstract":"Targeting the tumor microenvironment (TME) is an attractive strategy for cancer therapy, as tumor cells in vivo are surrounded by many different influential cell types, with complex interactions strongly affecting tumor progression and therapeutic outcome. Cancer-associated fibroblasts (CAFs) represent an abundant stromal cell type in the TME that modulate tumor development by exerting an immunosuppressive effect to influence effector immune cell activation. One promising target for TME-directed therapy is the CAF marker fibroblast activation protein-α (FAP). In this study, we employ a multicellular three-dimensional (3D) spheroid model, including tumor cells, fibroblast cells, and naïve T cells and could observe a protective effect of fibroblasts on tumor cells. Subsequently, we demonstrate that fibroblasts express FAP at differing expression levels in two-dimensional (2D) versus 3D cells. Lastly, we show that in a triple-culture of tumor cells, T cells and fibroblasts, the simultaneous assembly of fibroblasts using the high-affinity ligand oncoFAP with an engineered α-CD3-scFv-Fc-dextran-oncoFAP construct resulted in effective T cell activation to augment immunogenicity. Overall, this model can be routinely used for preclinical screening to study the effects of fibroblasts on the TME in vitro.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mimicking the immunosuppressive impact of fibroblasts in a 3D multicellular spheroid model\",\"authors\":\"Melanie Grotz, Lieke van Gijzel, Peter Bitsch, Stefania C. Carrara, Harald Kolmar, Sakshi Garg\",\"doi\":\"10.3389/fddsv.2024.1427407\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Targeting the tumor microenvironment (TME) is an attractive strategy for cancer therapy, as tumor cells in vivo are surrounded by many different influential cell types, with complex interactions strongly affecting tumor progression and therapeutic outcome. Cancer-associated fibroblasts (CAFs) represent an abundant stromal cell type in the TME that modulate tumor development by exerting an immunosuppressive effect to influence effector immune cell activation. One promising target for TME-directed therapy is the CAF marker fibroblast activation protein-α (FAP). In this study, we employ a multicellular three-dimensional (3D) spheroid model, including tumor cells, fibroblast cells, and naïve T cells and could observe a protective effect of fibroblasts on tumor cells. Subsequently, we demonstrate that fibroblasts express FAP at differing expression levels in two-dimensional (2D) versus 3D cells. Lastly, we show that in a triple-culture of tumor cells, T cells and fibroblasts, the simultaneous assembly of fibroblasts using the high-affinity ligand oncoFAP with an engineered α-CD3-scFv-Fc-dextran-oncoFAP construct resulted in effective T cell activation to augment immunogenicity. Overall, this model can be routinely used for preclinical screening to study the effects of fibroblasts on the TME in vitro.\",\"PeriodicalId\":73080,\"journal\":{\"name\":\"Frontiers in drug discovery\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-07-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in drug discovery\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3389/fddsv.2024.1427407\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in drug discovery","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3389/fddsv.2024.1427407","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

以肿瘤微环境(TME)为靶点是一种极具吸引力的癌症治疗策略,因为体内的肿瘤细胞被许多不同的有影响力的细胞类型所包围,它们之间复杂的相互作用对肿瘤的进展和治疗效果有很大影响。癌症相关成纤维细胞(CAFs)代表了TME中丰富的基质细胞类型,它们通过发挥免疫抑制作用来影响效应免疫细胞的活化,从而调节肿瘤的发展。CAF标记物成纤维细胞活化蛋白-α(FAP)是TME定向治疗的一个有希望的靶点。在这项研究中,我们采用了多细胞三维(3D)球形模型,包括肿瘤细胞、成纤维细胞和幼稚T细胞,并观察到成纤维细胞对肿瘤细胞的保护作用。随后,我们证明成纤维细胞在二维(2D)和三维细胞中表达 FAP 的水平不同。最后,我们表明,在肿瘤细胞、T 细胞和成纤维细胞的三重培养中,成纤维细胞使用高亲和性配体 oncoFAP 与工程化 α-CD3-scFv-Fc-dextran-oncoFAP 构建物同时组装,可有效激活 T 细胞,增强免疫原性。总之,该模型可常规用于临床前筛选,以研究成纤维细胞对体外 TME 的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mimicking the immunosuppressive impact of fibroblasts in a 3D multicellular spheroid model
Targeting the tumor microenvironment (TME) is an attractive strategy for cancer therapy, as tumor cells in vivo are surrounded by many different influential cell types, with complex interactions strongly affecting tumor progression and therapeutic outcome. Cancer-associated fibroblasts (CAFs) represent an abundant stromal cell type in the TME that modulate tumor development by exerting an immunosuppressive effect to influence effector immune cell activation. One promising target for TME-directed therapy is the CAF marker fibroblast activation protein-α (FAP). In this study, we employ a multicellular three-dimensional (3D) spheroid model, including tumor cells, fibroblast cells, and naïve T cells and could observe a protective effect of fibroblasts on tumor cells. Subsequently, we demonstrate that fibroblasts express FAP at differing expression levels in two-dimensional (2D) versus 3D cells. Lastly, we show that in a triple-culture of tumor cells, T cells and fibroblasts, the simultaneous assembly of fibroblasts using the high-affinity ligand oncoFAP with an engineered α-CD3-scFv-Fc-dextran-oncoFAP construct resulted in effective T cell activation to augment immunogenicity. Overall, this model can be routinely used for preclinical screening to study the effects of fibroblasts on the TME in vitro.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信