糖皮质激素联合免疫检查点抑制剂对淋巴细胞活化基因-3和程序性死亡-1表达的缓解作用

IF 3.7 3区 医学 Q2 IMMUNOLOGY
Smadar Gertel, Ari Polachek, Victoria Furer, Tali Ofir Dovrat, Chen Avaky, Adi Broyde, Hila Nochimovitz, Ori Elkayam
{"title":"糖皮质激素联合免疫检查点抑制剂对淋巴细胞活化基因-3和程序性死亡-1表达的缓解作用","authors":"Smadar Gertel,&nbsp;Ari Polachek,&nbsp;Victoria Furer,&nbsp;Tali Ofir Dovrat,&nbsp;Chen Avaky,&nbsp;Adi Broyde,&nbsp;Hila Nochimovitz,&nbsp;Ori Elkayam","doi":"10.1002/eji.70033","DOIUrl":null,"url":null,"abstract":"<p>Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, <i>p </i>&lt; 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4<sup>+</sup>LAG-3<sup>+</sup> T cells (4.9±1.2%, <i>p </i>&lt; 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4<sup>+</sup>PD-1<sup>+</sup> T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14<sup>+</sup>LAG-3<sup>+</sup> cells in SFMCs (10.4 ± 2.0%, <i>p </i>&lt; 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14<sup>+</sup>PD-1<sup>+</sup> cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4<sup>+</sup>LAG-3<sup>+</sup> T and CD14<sup>+</sup>LAG-3<sup>+</sup> cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 8","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70033","citationCount":"0","resultStr":"{\"title\":\"The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene-3 and Programmed Death-1 Expression\",\"authors\":\"Smadar Gertel,&nbsp;Ari Polachek,&nbsp;Victoria Furer,&nbsp;Tali Ofir Dovrat,&nbsp;Chen Avaky,&nbsp;Adi Broyde,&nbsp;Hila Nochimovitz,&nbsp;Ori Elkayam\",\"doi\":\"10.1002/eji.70033\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, <i>p </i>&lt; 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4<sup>+</sup>LAG-3<sup>+</sup> T cells (4.9±1.2%, <i>p </i>&lt; 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4<sup>+</sup>PD-1<sup>+</sup> T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14<sup>+</sup>LAG-3<sup>+</sup> cells in SFMCs (10.4 ± 2.0%, <i>p </i>&lt; 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14<sup>+</sup>PD-1<sup>+</sup> cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4<sup>+</sup>LAG-3<sup>+</sup> T and CD14<sup>+</sup>LAG-3<sup>+</sup> cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.</p>\",\"PeriodicalId\":165,\"journal\":{\"name\":\"European Journal of Immunology\",\"volume\":\"55 8\",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-08-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70033\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/eji.70033\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Immunology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/eji.70033","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

使用免疫检查点抑制剂(ICI)进行癌症免疫治疗显示出良好的治疗效果,但可能导致免疫相关不良事件(irAEs)。糖皮质激素(GCs)通常与ICI一起使用以减轻irae。我们之前发现,GCs在外周血和滑液单核细胞(分别为PBMCs和SFMCs)中显著上调抑制分子淋巴细胞活化基因-3 (LAG-3)。在这里,我们研究了GCs联合ICI对32例炎性关节炎患者SFMCs和15例健康对照PBMCs中LAG-3和程序性死亡-1 (PD-1)表达的影响。与单独使用PEM相比,GC+Pembrolizumab (PEM,抗pd -1)在pbmc和sfmc中诱导IL-10并抑制IFN-γ、TNF-α和IL-17A mRNA的表达。GC+PEM显著抑制PBMC增殖(3.5±0.7%,p <;0.0006),与单纯PEM相比(26.2±6.5%)。GC+PEM增加CD4+LAG-3+ T细胞(4.9±1.2%,p <;0.03)(0.9±0.3%),但对CD4+PD-1+ T细胞无影响。药物对滑膜细胞的影响显示,GC+PEM显著增加SFMCs中CD14+LAG-3+细胞(10.4±2.0%,p <;0.0001),与单纯PEM相比(0.6±0.2%),而CD14+PD-1+细胞无显著差异。因此,GC联合ICI可能通过分别上调循环和滑膜环境中的CD4+LAG-3+ T和CD14+LAG-3+细胞而表现出截然不同的活性,可能干扰了ICI活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene-3 and Programmed Death-1 Expression

The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene-3 and Programmed Death-1 Expression

Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, p < 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4+LAG-3+ T cells (4.9±1.2%, p < 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4+PD-1+ T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14+LAG-3+ cells in SFMCs (10.4 ± 2.0%, p < 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14+PD-1+ cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4+LAG-3+ T and CD14+LAG-3+ cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.

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
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
×
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