NK cell heparanase controls tumor invasion and immune surveillance
Eva M. Putz, … , Mark D. Hulett, Mark J. Smyth
Eva M. Putz, … , Mark D. Hulett, Mark J. Smyth
Published June 5, 2017
Citation Information: J Clin Invest. 2017;127(7):2777-2788. https://doi.org/10.1172/JCI92958.
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Research Article Immunology Oncology

NK cell heparanase controls tumor invasion and immune surveillance

Abstract

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.

Authors

Eva M. Putz, Alyce J. Mayfosh, Kevin Kos, Deborah S. Barkauskas, Kyohei Nakamura, Liam Town, Katharine J. Goodall, Dean Y. Yee, Ivan K.H. Poon, Nikola Baschuk, Fernando Souza-Fonseca-Guimaraes, Mark D. Hulett, Mark J. Smyth

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Figure 2

NK cell–intrinsic heparanase is indispensable for efficient surveillance of MCA-induced fibrosarcoma and RAE-1–expressing lymphoma.

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NK cell–intrinsic heparanase is indispensable for efficient surveillance...
(A–C) Hpsefl/fl NKp46-WT and Hpsefl/fl NKp46-iCre mice were inoculated s.c. in the hind flank with 100 μg MCA in 0.1 ml corn oil. Mice were then monitored over a 200-day period for fibrosarcoma development. Tumors were measured every week with a caliper (n = 24–28 per group; data were pooled from 2 independent experiments). (A) Data were recorded as the percentage of tumor-free mice (tumors were defined as measuring >3 mm in diameter and consistently growing). Tumor growth curves of individual (B) Hpsefl/fl NKp46-WT and (C) Hpsefl/fl NKp46-iCre mice. (D) Hpsefl/fl NKp46-WT and Hpsefl/fl NKp46-iCre mice were injected s.c. with 5 × 106 RMA-S-RAE-1β cells. Tumor growth was measured every 2 to 3 days with a caliper (mean ± SEM; n = 7 per group; 1 representative experiment of 2 experiments). Statistically significant differences were determined by log-rank Mantel-Cox test (A) and Mann-Whitney U test (D). *P < 0.05, **P < 0.01, and ****P < 0.0001.