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Targeting colon cancer cell NF-κB promotes an anti-tumour M1-like macrophage phenotype and inhibits peritoneal metastasis

Oncogene volume 34, pages 1563–1574 (2015)Cite this article

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Abstract

In a model of peritoneal metastasis in immune-competent mice, we show that nuclear factor (NF)-κB inhibition in CT26 colon cancer cells prevents metastasis. NF-κB inhibition, by stable overexpression of IκB-α super-repressor, induced differential polarization of co-cultured macrophages to an M1-like anti-tumour phenotype in vitro. NF-κB-deficient cancer cell-conditioned media (CT26/IκB-α SR) induced interleukin (IL)-12 and nitric oxide (NO) synthase (inducible NO synthase (iNOS)) expression in macrophages. Control cell (CT26/EV) conditioned media induced high levels of IL-10 and arginase in macrophages. In vivo, this effect translated to reduction in metastasis in mice injected with CT26/ IκB-α SR cells and was positively associated with increased CD8+CD44+CD62L− and CD4+CD44+CD62L− effector T cells. Furthermore, inhibition of NF-κB activity induced high levels of NO in infiltrating immune cells and decreases in matrix metalloproteinase-9 expression, simultaneous with increases in tissue inhibitor of metalloproteinases 1 and 2 within tumours. CT26/IκB-α SR tumours displayed increased pro-inflammatory gene expression, low levels of angiogenesis and extensive intratumoral apoptosis, consistent with the presence of an anti-tumour macrophage phenotype. Macrophage depletion reduced tumour size in CT26/EV-injected animals and increased tumour size in CT26/IκB-α SR cells compared with untreated tumours. Our data demonstrate, for the first time, that an important implication of targeting tumour cell NF-κB is skewing of macrophage polarization to an anti-tumour phenotype. This knowledge offers novel therapeutic opportunities for anticancer treatment.

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Acknowledgements

This work was supported by funding from the Irish Cancer Society to AER (CRF12RYA) and from the Science Foundation Ireland (04/IN3/B748) and the Irish Cancer Society to LJE.

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Authors and Affiliations

  1. Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland,

    A E Ryan, A Colleran, A O'Gorman, G O'Malley, C Mureau & L J Egan

  2. Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland

    A E Ryan, L O'Flynn, J Pindjacova, P Lohan, G O'Malley & M Nosov

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  1. A E Ryan
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Correspondence to L J Egan.

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Ryan, A., Colleran, A., O'Gorman, A. et al. Targeting colon cancer cell NF-κB promotes an anti-tumour M1-like macrophage phenotype and inhibits peritoneal metastasis. Oncogene 34, 1563–1574 (2015). https://doi.org/10.1038/onc.2014.86

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