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 Article has an altmetric score of 4

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 3

Heparanase-deficient NK cells display impaired control of lung metastases.

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Heparanase-deficient NK cells display impaired control of lung metastase...
(A) Hpsefl/fl NKp46-WT, Hpsefl/fl NKp46-iCre, HpseWT/WT NKp46-WT (B6.WT), and HpseWT/WT NKp46-iCre mice were injected i.v. with 1 × 105 RM-1 prostate carcinoma cells. Lungs were harvested on day 14 and macrometastases counted (mean ± SEM; n = 4–16 mice per group; data were pooled from 2 independent experiments). (B) Hpsefl/fl NKp46-WT, Hpsefl/fl NKp46-iCre, HpseWT/WT NKp46-WT (B6.WT), and HpseWT/WT NKp46-iCre mice were injected i.v. with 2 × 105 B16F10 melanoma cells. Lungs were harvested on day 14 and macrometastases counted (mean ± SEM; n = 6–22 mice per group; data were pooled from 3 independent experiments). (C) Hpsefl/fl NKp46-WT and Hpsefl/fl NKp46-iCre mice were injected with 2 × 104 E0771 cells into the mammary fat pad and treated with either 50 μg control Ig (–) or anti–asialo-GM1 (+) (NK cell depletion) on days –1, 0, 7, 14, and 23 after tumor transplantation. Tumors were removed surgically on day 12. Lungs were harvested on day 35 and macrometastases counted (mean ± SEM; n = 6–8 mice per group). (D) Hpsefl/fl NKp46-WT and Hpsefl/fl NKp46-iCre mice were injected i.v. with 5 × 105 B16F10 melanoma cells and treated i.p. with either PBS or 100,000 IU IL-2 on days 0, 1, 2, 3, and 4. Lungs were harvested on day 14 and macrometastases counted (mean ± SEM; n = 10–11 mice per group; data were pooled from 2 independent experiments). (E) Hpsefl/fl NKp46-WT and Hpsefl/fl NKp46-iCre mice were injected i.v. with 5 × 105 B16F10 melanoma cells and treated with either 500 μg control Ig (–) or 250 μg each of anti-CTLA4 and anti–PD-1 (+) on days 0 and 3 after injection, respectively. Lungs were harvested on day 14 and macrometastases counted (mean ± SEM; n = 5–7 mice per group). (A–E) Statistically significant differences between the groups were determined by 1-way ANOVA with Tukey’s post test (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001).