ISLR knockdown enhances radiotherapy-induced anti-tumor immunity by disrupting the Treg-mregDC-lymphoid niche in triple-negative breast cancer

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-06-14 DOI:10.1016/j.intimp.2025.114988

Shuai Wang , Yang Wang , Yulan Bu , Xuxin Duan , Xiangxiang Guo , Wenliang Wu , Houfa Ning

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引用次数: 0

Abstract

Background

Triple-negative breast cancer (TNBC) is characterized by an immunosuppressive tumor microenvironment (TME) that hinders the efficacy of immunotherapy. Recent findings suggest that the interaction between ISLR and the MIF/CD74 signaling pathway plays a pivotal role in immune evasion. This study explores how radiotherapy (RT) modulates ISLR expression and its subsequent impact on immunotherapeutic outcomes in TNBC.

Methods

A multi-omics approach was employed, incorporating single-cell RNA sequencing (scRNA-seq) and transcriptomic datasets. The role of ISLR in the MIF/CD74 signaling axis was validated in TNBC cell lines and mouse xenograft models. In vitro, ISLR expression was either knocked down or overexpressed in MDA-MB-231 cells, followed by exposure to RT at doses of 5 Gy or 10 Gy. Cellular proliferation, migration, and cytokine secretion were subsequently assessed. In vivo, TNBC-bearing mice received RT and/or PD-1 immune checkpoint inhibitors. Tumor growth, immune cell infiltration, and DNA damage were evaluated.

Results

RT markedly reduced ISLR expression, thereby disrupting the MIF/CD74 signaling pathway and attenuating the formation of the Treg-mregDC-lymphoid niche. ISLR knockdown led to decreased secretion of IL-10 and TGF-β, while promoting CD8⁺ T cell infiltration and enhancing anti-tumor immune responses. Mechanistic studies revealed that ISLR directly interacts with CD74 and regulates its transcriptional activity. In vivo, ISLR knockdown in combination with RT significantly suppressed tumor growth and improved the efficacy of PD-1 blockade.

Conclusions

ISLR serves as a crucial regulator of immune evasion in TNBC by modulating the MIF/CD74 signaling pathway and promoting an immunosuppressive TME. Targeting ISLR amplifies the immunogenic effects of RT and enhances the response to immunotherapy, offering a promising therapeutic strategy for TNBC management.

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在三阴性乳腺癌中，ISLR敲低通过破坏treg - mregdc淋巴细胞生态位增强放疗诱导的抗肿瘤免疫

三阴性乳腺癌（TNBC）的特点是免疫抑制肿瘤微环境（TME）阻碍了免疫治疗的效果。最近的研究结果表明，ISLR与MIF/CD74信号通路之间的相互作用在免疫逃避中起着关键作用。本研究探讨了放疗（RT）如何调节TNBC中ISLR的表达及其对免疫治疗结果的后续影响。方法采用多组学方法，结合单细胞RNA测序（scRNA-seq）和转录组学数据集。在TNBC细胞系和小鼠异种移植模型中证实了ISLR在MIF/CD74信号轴中的作用。在体外，MDA-MB-231细胞中的ISLR表达被下调或过表达，随后暴露于5 Gy或10 Gy剂量的RT中。随后评估细胞增殖、迁移和细胞因子分泌。在体内，携带tnbc的小鼠接受了RT和/或PD-1免疫检查点抑制剂。评估肿瘤生长、免疫细胞浸润和DNA损伤。结果rt显著降低了ISLR的表达，从而破坏了MIF/CD74信号通路，减弱了treg - mregdc淋巴细胞生态位的形成。ISLR敲低导致IL-10和TGF-β分泌减少，促进CD8+ T细胞浸润，增强抗肿瘤免疫应答。机制研究表明，ISLR直接与CD74相互作用并调节其转录活性。在体内，ISLR敲低联合RT可显著抑制肿瘤生长，提高PD-1阻断的疗效。结论islr通过调节MIF/CD74信号通路，促进免疫抑制TME，在TNBC中起重要的免疫逃避调节作用。靶向ISLR增强了RT的免疫原性作用，增强了对免疫治疗的反应，为TNBC的治疗提供了一种有前景的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.