CSF1R-dependent myeloid cells are required for NK‑mediated control of metastasis
Michal Beffinger, … , Anurag Gupta, Maries van den Broek
Michal Beffinger, … , Anurag Gupta, Maries van den Broek
Published May 17, 2018
Citation Information: JCI Insight. 2018;3(10):e97792. https://doi.org/10.1172/jci.insight.97792.
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Research Article Immunology Oncology

CSF1R-dependent myeloid cells are required for NK‑mediated control of metastasis

Abstract

Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases. Supplementation of mice treated with CSF1R-inhibitor with IL-15 restored numbers of NK cells and diminished metastasis. Our data suggest that CSF1R blockade should be combined with administration of IL-15 to reduce the risk of metastasis.

Authors

Michal Beffinger, Paulino Tallón de Lara, Sònia Tugues, Marijne Vermeer, Yannick Montagnolo, Isabel Ohs, Virginia Cecconi, Giulia Lucchiari, Aron Gagliardi, Nikola Misljencevic, James Sutton, Roman Spörri, Burkhard Becher, Anurag Gupta, Maries van den Broek

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Figure 3

Administration of CSF1Ri promotes metastasis via concomitant loss of NK cells.

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Administration of CSF1Ri promotes metastasis via concomitant loss of NK ...
(A) LLC-LUC cells were i.v. injected into C57BL/6 mice that were depleted of CD4+ or CD8+ cells. The metastatic burden was determined 24 hours (endpoint 1) or 16 days (endpoint 2) after tumor cell injection by bioluminescent imaging on resected lungs. Each symbol represents an individual mouse. Endpoint 1, Ctrl and aCD4, n = 4; aCD8, n = 5. Endpoint 2, Ctrl, n = 8; aCD8, n = 6. Mean ± SD. Groups are not statistically significantly different (1-way ANOVA with Bonferroni’s correction). (B) LLC-LUC cells were i.v. injected into C57BL/6 mice that were depleted of NK cells immediately before or afterward. The metastatic burden was determined 14 days after tumor cell injection by bioluminescent imaging on resected lungs. Each symbol represents an individual mouse. Ctrl and +24 hours, n = 6; –24 hours, n = 5. Mean ± SD. **P < 0.01 (one-way ANOVA with Bonferroni’s correction). (C) LLC-LUC cells were i.v. injected into NK cell–depleted C57BL/6 mice. The metastatic burden was determined 20 minutes and 1 hour after tumor cell injection by bioluminescent imaging on resected lungs. Each symbol represents an individual mouse. Twenty minutes, Ctrl, n = 5; aNK1.1, n = 6. Twenty-four hours, Ctrl, n = 3; aNK1.1, n = 4. Mean ± SD. *P < 0.05 (2-tailed Student’s t test with Welch’s correction). (D) Mice bearing s.c. LLC-LUC tumors were depleted from NK cells before resection. Lower left panel: Number of NK cells in the resected tumor. Each symbol represents an individual mouse. Ctrl and aNK1.1, n = 8. Mean ± SD. *P < 0.05 (2-tailed Student’s t test with Welch’s correction). Lower right panel: Spontaneous metastasis to the lungs is presented as sum of luminescent signals from lung, liver, and both tumor-draining lymph nodes for each mouse. Filled circles represent mice with detectable metastasis; open circles represent metastasis-free mice. Mice above the dotted line had to be sacrifice before the endpoint due to metastatic burden. Numbers above the graph show number of mice with metastasis in total cohort of animals (Ctrl and aNK.1.1, n = 14). **P < 0.01 (χ2 test). (E) Metastatic seeding to the lungs measured 1 day after i.v. injection of LLC-LUC cells into NK cell–depleted, CSF1Ri-treated, or control mice. The left panel shows the number of circulating NK cells at day 0. The right panel shows the metastatic burden to the lungs measured by bioluminescent imaging on resected lungs. Each symbol represents an individual mouse. Ctrl, n = 9; aNK.1.1, n = 4; CSF1Ri, n = 9. Mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.005 (1-way ANOVA with Bonferroni’s correction). A representative experiment of 2 is shown.