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

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

  2. Author Address

    Women 39;s Malignancies Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA., Center for Cancer Research Collaborative Bioinformatics Resource (CCBR), NCI, NIH, Bethesda, MD, USA., Cancer Innovation Laboratory, Center for Cancer Research (CCR), NCI, NIH, Frederick, MD, USA., Center for Immuno-Oncology, CCR, NCI, NIH, Bethesda, MD, USA., Laboratory of Cellular and Molecular Biology, CCR, NCI, NIH, Bethesda, MD, USA., Computational Genomics and Bioinformatics Branch, Center for Biomedical Informatics and Information Technology (CBIIT), NCI, NIH, Rockville, MD, USA., Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Women 39;s Malignancies Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address: lipkowis@navmed.nci.nih.gov.,
    1. Year: 2025
    2. Date: Jun 28
    3. Epub Date: 2025 04 03
  2. Journal: Cancer Letters
    1. 620
    2. Pages: 217692
  4. Type of Article: Article
  5. Article Number: 217692
  1. 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. Copyright © 2025. Published by Elsevier B.V.

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External Sources

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  2. DOI: 10.1016/j.canlet.2025.217692
  3. PMID: 40187604
  4. PII : S0304-3835(25)00258-7

Library Notes

  1. Fiscal Year: FY2024-2025
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