The Influence of Indisulam on Human Immune Effector Cells: Is a Combination with Immunotherapy Feasible?

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Lisa Arnet, Lisabeth Emilius, Annett Hamann, Maria Carmo-Fonseca, Carola Berking, Jan Dörrie, Niels Schaft
{"title":"The Influence of Indisulam on Human Immune Effector Cells: Is a Combination with Immunotherapy Feasible?","authors":"Lisa Arnet, Lisabeth Emilius, Annett Hamann, Maria Carmo-Fonseca, Carola Berking, Jan Dörrie, Niels Schaft","doi":"10.3390/pharmaceutics17030368","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> As a modulator of pre-mRNA splicing, the anti-cancer agent indisulam can induce aberrantly spliced neoantigens, enabling immunologic anti-tumor activity. Consequently, combining indisulam with immunotherapy is expected to be a promising novel approach in cancer therapy. However, a prerequisite for such a combination is that immune effector cells remain functional and unharmed by the chemical. <b>Methods:</b> To ensure the immunocompetence of human immune effector cells is maintained, we investigated the influence of indisulam on ex vivo-isolated T cells and monocyte-derived dendritic cells (moDCs) from healthy donors. We used indisulam concentrations from 0.625 µM to 160 µM and examined the impact on the following: (i) the activation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells by CD3-crosslinking and via a high-affinity TCR, (ii) the cytotoxicity of CD8<sup>+</sup> T cells, (iii) the maturation process of moDCs, and (iv) antigen-specific CD8<sup>+</sup> T cell priming. <b>Results:</b> We observed dose-dependent inhibitory effects of indisulam, and substantial inhibition occurred at concentrations around 10 µM, but the various functions of the immune system exhibited different sensitivities. The weaker activation of T cells via CD3-crosslinking was more sensitive than the stronger activation via the high-affinity TCR. T cells remained capable of killing tumor cells after treatment with indisulam up to 40 µM, but T cell cytotoxicity was impaired at 160 µM indisulam. While moDC maturation was also rather resistant, T cell priming was almost completely abolished at a concentration of 10 µM. <b>Conclusions:</b> These effects should be considered in possible future combinations of immunotherapy with the mRNA splicing inhibitor indisulam.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945250/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/pharmaceutics17030368","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: As a modulator of pre-mRNA splicing, the anti-cancer agent indisulam can induce aberrantly spliced neoantigens, enabling immunologic anti-tumor activity. Consequently, combining indisulam with immunotherapy is expected to be a promising novel approach in cancer therapy. However, a prerequisite for such a combination is that immune effector cells remain functional and unharmed by the chemical. Methods: To ensure the immunocompetence of human immune effector cells is maintained, we investigated the influence of indisulam on ex vivo-isolated T cells and monocyte-derived dendritic cells (moDCs) from healthy donors. We used indisulam concentrations from 0.625 µM to 160 µM and examined the impact on the following: (i) the activation of CD4+ and CD8+ T cells by CD3-crosslinking and via a high-affinity TCR, (ii) the cytotoxicity of CD8+ T cells, (iii) the maturation process of moDCs, and (iv) antigen-specific CD8+ T cell priming. Results: We observed dose-dependent inhibitory effects of indisulam, and substantial inhibition occurred at concentrations around 10 µM, but the various functions of the immune system exhibited different sensitivities. The weaker activation of T cells via CD3-crosslinking was more sensitive than the stronger activation via the high-affinity TCR. T cells remained capable of killing tumor cells after treatment with indisulam up to 40 µM, but T cell cytotoxicity was impaired at 160 µM indisulam. While moDC maturation was also rather resistant, T cell priming was almost completely abolished at a concentration of 10 µM. Conclusions: These effects should be considered in possible future combinations of immunotherapy with the mRNA splicing inhibitor indisulam.

吲哚兰对人免疫效应细胞的影响:与免疫疗法联合用药是否可行?
背景:作为pre-mRNA剪接的调节剂,抗癌药物吲哚南可以诱导剪接异常的新抗原,从而具有免疫抗肿瘤活性。因此,免疫治疗与吲哚南联合治疗有望成为一种有前景的癌症治疗新方法。然而,这种组合的先决条件是免疫效应细胞保持功能,不受化学物质的伤害。方法:为了维持人免疫效应细胞的免疫能力,我们研究了胰岛素对健康供体离体T细胞和单核细胞来源的树突状细胞(moDCs)的影响。我们使用浓度从0.625µM到160µM的胰岛素,并检查了对以下方面的影响:(i)通过cd3交联和高亲和TCR激活CD4+和CD8+ T细胞,(ii) CD8+ T细胞的细胞毒性,(iii) moDCs的成熟过程,以及(iv)抗原特异性CD8+ T细胞启动。结果:我们观察到吲哚南的剂量依赖性抑制作用,在10µM左右的浓度下出现实质性的抑制作用,但免疫系统的各种功能表现出不同的敏感性。cd3交联对T细胞的弱激活比高亲和力TCR对T细胞的强激活更敏感。注射40µM胰岛素后,T细胞仍能杀死肿瘤细胞,但注射160µM胰岛素后,T细胞的细胞毒性受损。虽然moDC成熟也具有相当的抗性,但在浓度为10µM时,T细胞启动几乎完全消失。结论:这些影响应考虑在未来可能的免疫治疗联合mRNA剪接抑制剂胰岛素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
×
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:604180095
Book学术官方微信