Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages

Kelly Kersten, Seth B. Coffelt, Marlous Hoogstraat, Niels J.M. Verstegen, Kim Vrijland, Metamia Ciampricotti, Chris W. Doornebal, Cheei-Sing Hau, Max D. Wellenstein, Camilla Salvagno, Parul Doshi, Esther H. Lips, Lodewyk Wessels, Karin E. de Visser*

*Corresponding author for this work

Research output: Contribution to journalArticleScientific

52 Citations (Scopus)
44 Downloads (Pure)

Abstract

Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer. How tumors orchestrate this systemic inflammatory cascade to facilitate dissemination remains unclear. Here we show that activation of this cascade relies on CCL2-mediated induction of IL1β in tumor-associated macrophages. In line with these findings, expression of CCL2 positively correlates with IL1Β and macrophage markers in human breast tumors. We demonstrate that blockade of CCL2 in mammary tumor-bearing mice results in reduced IL17 production by γδ T cells, decreased neutrophil expansion and enhanced CD8+ T cell activity. These results highlight a new role for CCL2 in facilitating the breast cancer-induced pro-metastatic systemic inflammatory γδ T cell–IL17–neutrophil axis.

Original languageEnglish
Article numbere1334744
JournalOncoImmunology
Volume6
Issue number8
DOIs
Publication statusPublished - 2017

Keywords

  • Breast cancer
  • CCL2
  • immunosuppression
  • neutrophils
  • tumor-associated macrophages
  • tumor-induced inflammation
  • γδ T cells

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