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

Kersten, K. et al. (2017) Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages. OncoImmunology, 6(8), e1334744. (doi: 10.1080/2162402X.2017.1334744) (PMID:28919995) (PMCID:PMC5593698)

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.

• Item Type: Articles
• Additional Information: This work was supported by a European Research Council Consolidator award (INFLAMET 615300) and grants from the Dutch Cancer Society (2011-5004); Worldwide Cancer Research (AICR 11–0677); the Netherlands Organization for Scientific Research NWO VIDI (917.96.307); the European Union (FP7 MCA-ITN 317445 TIMCC) to K.E.dV., and a Dutch Cancer Society grant (2013-6007) to L.F.A.W.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coffelt, Professor Seth
• Authors: Kersten, K., Coffelt, S. B., Hoogstraat, M., Verstegen, N. J.M., Vrijland, K., Ciampricotti, M., Doornebal, C. W., Hau, C.-S., Wellenstein, M. D., Salvagno, C., Doshi, P., Lips, E. H., Wessels, L. F.A., and de Visser, K. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: OncoImmunology
• Publisher: Taylor & Francis
• ISSN: 2162-4011
• ISSN (Online): 2162-402X
• Published Online: 19 June 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in OncoImmunology 6(8): e1334744
• Publisher Policy: Reproduced under a Creative Commons license