Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation

• Published in: The Journal of clinical investigation Vol. 126; no. 1; pp. 207 - 219
• Main Authors: Brennan, Todd V, Lin, Liwen, Brandstadter, Joshua D, Rendell, Victoria R, Dredge, Keith, Huang, Xiaopei, Yang, Yiping
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2016
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Biomedical research; Cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Development and progression; Growth factors; Heparitin Sulfate - pharmacology; Humans; Interleukin-12 - biosynthesis; Killer Cells, Natural - immunology; Lymphocyte Activation - drug effects; Lymphocytes; Lymphoma; Lymphoma - drug therapy; Lymphoma - immunology; Lysosomes - metabolism; Medical prognosis; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid Differentiation Factor 88 - physiology; Non-Hodgkin's lymphomas; Oligodeoxyribonucleotides - pharmacology; Patient outcomes; Phosphatase; Saponins - pharmacology; Software; Studies; Sulfates; Toll-Like Receptor 9 - physiology; Tumors; China
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI76566

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.