TRAIL induces cytokine production via the NFkB2 pathway promoting neutrophil chemotaxis and neutrophil-mediated immune-suppression in triple negative breast cancer cells

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-04-03 DOI:10.1016/j.canlet.2025.217692

Manjari Kundu , Yoshimi E. Greer , Alexei Lobanov , Lisa Ridnour , Renee N. Donahue , Yeap Ng , Shashi Ratnayake , Karley White , Donna Voeller , Sarah Weltz , Qingrong Chen , Stephen J. Lockett , Maggie Cam , Daoud Meerzaman , David A. Wink , Roberto Weigert , Stanley Lipkowitz

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引用次数: 0

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic that induces apoptosis in cancer cells while sparing the non-malignant cells in preclinical models. However, its efficacy in clinical trials has been limited, suggesting unknown mechanisms modulating TRAIL activity in patients. We hypothesized that TRAIL treatment elicits transcriptional changes in triple negative breast cancer (TNBC) cells that alter the immune milieu. RNAseq analysis of MDA-MB-231 cells along with validation in additional cell lines demonstrated that TRAIL induced cytokines such as CXCLs 1, 2, 3, 8,11 and IL-6, which are known to modify neutrophil function. Mechanistically, TRAIL dependent induction of the cytokines was predominantly mediated by death receptor 5, caspase-8 and the non-canonical NFKB2 pathway. These cytokines produced by TRAIL-treated TNBC cells enhanced chemotaxis of normal human donor isolated neutrophils. Using TNBC xenograft models, TRAIL induced activation of NFkB2 pathway, cytokine production and increased neutrophil recruitment into the tumors. Moreover, preincubation of neutrophils in supernatants from TRAIL-treated TNBC cells significantly impaired neutrophil function as measured by reduced respiratory burst and cytotoxic effect against TNBC cells. Transcriptomic analysis of neutrophils incubated with either TRAIL alone or supernatant of TRAIL-treated TNBC cells revealed increased expression of inflammatory cytokines, immune modulatory genes, immune checkpoint genes, and genes implicated in delayed neutrophil apoptosis. Functional studies showed that these neutrophils suppress T cell proliferation and augment Treg suppressive phenotype. Collectively, our study demonstrates a novel role of TRAIL-induced NFKB2-dependent cytokine production that promotes neutrophil chemotaxis and neutrophil- mediated immune suppression.

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TRAIL通过NFkB2途径诱导细胞因子产生，促进中性粒细胞趋化和中性粒细胞介导的三阴性乳腺癌细胞免疫抑制。

肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）是一种潜在的癌症治疗药物，在临床前模型中可诱导癌细胞凋亡，同时保留非恶性细胞。然而，其在临床试验中的疗效有限，提示未知的机制调节患者的TRAIL活性。我们假设TRAIL治疗引起三阴性乳腺癌（TNBC）细胞的转录改变，从而改变免疫环境。MDA-MB-231细胞的RNAseq分析以及在其他细胞系中的验证表明，TRAIL诱导细胞因子如CXCLs 1、2、3、8、11和IL-6，这些细胞因子已知可修饰中性粒细胞功能。在机制上，TRAIL依赖的细胞因子诱导主要由死亡受体5、caspase-8和非典型NFKB2途径介导。trail处理的TNBC细胞产生的这些细胞因子增强了正常人类供体分离的中性粒细胞的趋化性。在TNBC异种移植模型中，TRAIL诱导NFkB2通路的激活、细胞因子的产生和中性粒细胞进入肿瘤的增加。此外，在trail处理的TNBC细胞的上清液中预孵育中性粒细胞显著损害中性粒细胞功能，通过减少呼吸爆发和对TNBC细胞的细胞毒性作用来测量。用TRAIL单独或TRAIL处理的TNBC细胞上清培养的中性粒细胞转录组学分析显示，炎症因子、免疫调节基因、免疫检查点基因和与中性粒细胞延迟凋亡有关的基因的表达增加。功能研究表明，这些中性粒细胞抑制T细胞增殖并增强Treg抑制表型。总之，我们的研究证明了trail诱导的nfkb2依赖性细胞因子产生的新作用，该细胞因子促进中性粒细胞趋化和中性粒细胞介导的免疫抑制。

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

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.