ArticleThe Journal of clinical investigation2016
Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
37 citing papers in PubMed, 64 citations in OpenAlex.
- Toll-like receptors: versatile players in tumor.Frontiers in immunology · 2026Review
- From Native Glycosaminoglycans to Mimetics: Design, Mechanisms, and Biomedical Applications.Biomolecules · 2025Review
- Natural killer cell-based cancer immunotherapy: from basics to clinical trials.Experimental hematology & oncology · 2024Review
- Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis.Nature communications · 2024Article
- TLR9 Monotherapy in Immune-Competent Mice Suppresses Orthotopic Prostate Tumor Development.Cells · 2024Article
- Disease pathology signatures in a mouse model of Mucopolysaccharidosis type IIIB.Scientific reports · 2023Article
- PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction.Oncogene · 2023Article
- Heparan sulfate proteoglycans in cancer: Pathogenesis and therapeutic potential.Advances in cancer research · 2023Article
- Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors.Journal for immunotherapy of cancer · 2023Article
- Review
- Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management.Biomolecules · 2021Review
- Natural killer cells in cancer biology and therapy.Molecular cancer · 2020Review
- Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer.Biochemical pharmacology · 2020Article
- Forty Years of Basic and Translational Heparanase Research.Advances in experimental medicine and biology · 2020Review
- Unleashing Natural Killer Cells in the Tumor Microenvironment-The Next Generation of Immunotherapy?Frontiers in immunology · 2020Review
- The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity.Frontiers in immunology · 2020Article
- Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends.Medicines (Basel, Switzerland) · 2019Review
- Circulating mitochondria in organ donors promote allograft rejection.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2019Article
- Targeting Heparanase in Cancer: Inhibition by Synthetic, Chemically Modified, and Natural Compounds.iScience · 2019Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.