CSF1R-dependent myeloid cells are required for NK‑mediated control of metastasis
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
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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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 1

Blocking CSF1R increases the risk of developing metastatic disease.

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Blocking CSF1R increases the risk of developing metastatic disease. (A–C...
(A–C) Spontaneous metastasis from s.c. LLC-LUC tumors in C57BL/6 mice. (A) Experimental timeline. (B) Primary tumor size at resection. Mean ± SD. Each symbol represents an individual mouse (Ctrl, n = 7; CSF1Ri, n = 6). Representative data from 2 independent experiments are shown. (C) Metastatic burden 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 sacrificed before the endpoint due to metastatic burden. Numbers above the graph show number of mice with metastasis in total cohort of animals. *P < 0.05 (χ2 test). Pooled data from 2 independent experiments are shown (Ctrl, n = 13; CSF1Ri, n = 17). (D–F) Spontaneous lung metastasis from autochthonous 4T1 tumors in BALB/c mice. (D) Experimental timeline. Mice were treated daily with a small-molecule inhibitor of CSF1R (E) or with blocking anti-CSF1R antibody on the indicated days (F). (E and F) Primary tumor weight at resection. Mean ± SD. Lung metastases quantified by bioluminescence. Mean ± SEM. *P < 0.05 (2-tailed Student’s t test with Welch’s correction). Each symbol represents an individual mouse. (E) Ctrl, n = 9; CSF1Ri, n = 10. (F) Ctrl and CSF1Ri, n = 11.