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 2

Administration of CSF1Ri results in concomitant loss of NK cells.

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Administration of CSF1Ri results in concomitant loss of NK cells. Admini...
Administration of CSF1Ri starting 8 days before resection results in loss of NK, CD8+, and myeloid cells in the tumor (A) and blood (B) as measured by flow cytometry. Ly6Chi and Ly6Clo cells represent inflammatory and patrolling monocytes, respectively. Monocytes, CD45.2+CD11b+CSF1R+; NK cells, CD45.2+CD3–NK1.1+; CD8+ T cells, CD45.2+CD3+CD8α+; neutrophils, CD45.2+CD11b+Ly6G+; B cells, CD45.2+CD19+; CD4+ T cells, CD45.2+CD3+CD4+. Analysis was performed after gating on live singlets. (C) Administration of CSF1Ri starting 8 days before resection results in selective loss of CSF1R+ cells from the CD11b+ population in the blood (left panels) and tumor (right panels). CSF1R expression was visualized using CSF1R-reporter mice (MacGreen). (A–C) Each symbol represents an individual mouse. (A) Ctrl and CSF1Ri, n = 11. (B and C) Ctrl and CSF1Ri, n = 7. Mean ± SD. **P < 0.01, ***P < 0.005 (2-tailed Student’s t test with Welch’s correction). A representative experiment of 2 is shown.