Investigating the key enzyme promoting NK cell infiltration into tumors

Among the different mechanisms that could prevent metastasis, understanding how immune cells infiltrate primary tumors is critical. Many solid tumors are encapsulated by a thick layer of the extracellular matrix (ECM), creating a dense barrier that is it particularly difficult for immune cells to cross. How to get to the other side of the wall? Make it more permeable?

Proteoglycan degradation and remodeling of the ECM is controlled by heparanase enzyme activity. Besides tumor cells, immune cells including natural killer (NK) cells also express this enzyme. Eva M. Putz et al. have decrypted the role of NK heparanase which is up-regulated during NK cell activation.

Using either human NK cells isolated from peripheral blood mononuclear cells (PBMCs), NK cells activated in-vitro, or genetically-modified mice lacking the HSPE gene, she demonstrates the key role played by NK cell heparanase in the degradation of the ECM. Not just breaking the wall…

Read more in this article and understand how maintaining or enhancing heparanase expression and activity in NK cells improves NK cell-based anticancer immunotherapy. A key and source of hope for new treatments.

Eva M. Putz et al.

2017

Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

J. Clin. Invest. 2017 Jun 30;127(7):2777-2788.

NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors. Here, have we demonstrated that freshly isolated mouse and human NK cells express low levels of the endo-β-D-glucuronidase heparanase that increase upon NK cell activation. Heparanase deficiency did not affect development, differentiation, or tissue localization of NK cells under steady-state conditions. However, mice lacking heparanase specifically in NK cells (Hpsefl/fl NKp46-iCre mice) were highly tumor prone when challenged with the carcinogen methylcholanthrene (MCA). Hpsefl/fl NKp46-iCre mice were also more susceptible to tumor growth than were their littermate controls when challenged with the established mouse lymphoma cell line RMA-S-RAE-1β, which overexpresses the NK cell group 2D (NKG2D) ligand RAE-1β, or when inoculated with metastatic melanoma, prostate carcinoma, or mammary carcinoma cell lines. NK cell invasion of primary tumors and recruitment to the site of metastasis were strictly dependent on the presence of heparanase. Cytokine and immune checkpoint blockade immunotherapy for metastases was compromised when NK cells lacked heparanase. Our data suggest that heparanase plays a critical role in NK cell invasion into tumors and thereby tumor progression and metastases. This should be considered when systemically treating cancer patients with heparanase inhibitors, since the potential adverse effect on NK cell infiltration might limit the antitumor activity of the inhibitors.

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