套细胞淋巴瘤细胞与淋巴瘤相关巨噬细胞之间的对话是伊布替尼耐药性的基础。

Xiaoqing Sun, Caiqin Wang, Jianghua Cao, Jing Li, Gang Ma, Xianqiu Wu, Peng Sun, Yu Wang, Jiajia Huang, Robert Peter Gale, Zhiming Li
{"title":"套细胞淋巴瘤细胞与淋巴瘤相关巨噬细胞之间的对话是伊布替尼耐药性的基础。","authors":"Xiaoqing Sun, Caiqin Wang, Jianghua Cao, Jing Li, Gang Ma, Xianqiu Wu, Peng Sun, Yu Wang, Jiajia Huang, Robert Peter Gale, Zhiming Li","doi":"10.1016/j.jare.2024.08.023","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature.</p><p><strong>Objectives: </strong>To elucidate the role of LAMs in mediating ibrutinib resistance in MCL.</p><p><strong>Methods: </strong>We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line.</p><p><strong>Results: </strong>In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone.</p><p><strong>Conclusion: </strong>Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.\",\"authors\":\"Xiaoqing Sun, Caiqin Wang, Jianghua Cao, Jing Li, Gang Ma, Xianqiu Wu, Peng Sun, Yu Wang, Jiajia Huang, Robert Peter Gale, Zhiming Li\",\"doi\":\"10.1016/j.jare.2024.08.023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature.</p><p><strong>Objectives: </strong>To elucidate the role of LAMs in mediating ibrutinib resistance in MCL.</p><p><strong>Methods: </strong>We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line.</p><p><strong>Results: </strong>In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone.</p><p><strong>Conclusion: </strong>Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.</p>\",\"PeriodicalId\":94063,\"journal\":{\"name\":\"Journal of advanced research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-08-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of advanced research\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jare.2024.08.023\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of advanced research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.jare.2024.08.023","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

简介:套细胞淋巴瘤(MCL)患者经常对依鲁替尼产生耐药性。淋巴瘤相关巨噬细胞(LAMs)可能在这种耐药性中起着因果作用,但目前的文献对此仍未进行深入探讨:阐明巨噬细胞在介导 MCL 中伊布替尼耐药性中的作用:方法:我们使用CD206和CD86抗体,通过多参数流式细胞术(MPFC)研究了对伊布替尼耐药和敏感的MCL患者血液和组织样本中巨噬细胞的极化。随后,我们利用 MCL 细胞系开发了一种体外共培养模型,以确定与伊布替尼耐药性和巨噬细胞 M2 极化相关的细胞因子。我们使用MPFC、RNA测序和Western印迹分析研究了耐药性的内在机制。此外,我们还通过CCK-8和caspase-3检测法以及伊布替尼耐药MCL细胞系的小鼠异种移植模型,评估了CXCR2抑制剂SB225002是否能逆转伊布替尼耐药:结果:在伊布替尼耐药患者中,M2与M1 LAM的比例明显高于敏感患者。在LAMs和MCL细胞的共培养中,M2巨噬细胞的比例、伊布替尼的IC50值以及IL-8和CXCL5的浓度都明显升高。从机制上讲,LAMs分泌的CXCL5与MCL细胞上的CXCR2相互作用,导致Akt、p38和STAT3信号通路在伊布替尼存在的情况下被激活;这种活性在CXCL5/CXCR2轴被阻断后减弱。与单用伊布替尼治疗相比,SB225002和伊布替尼联合治疗可显著增强MCL细胞凋亡,抑制异种移植模型中淋巴瘤的生长,并重塑巨噬细胞表型:我们的数据表明,在MCL模型中,M2极化的LAMs与伊布替尼耐药有关,而CXCR2抑制剂可以逆转这种耐药。这些发现提出了一种潜在的新治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.

Introduction: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature.

Objectives: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL.

Methods: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line.

Results: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone.

Conclusion: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

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