Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10
Article first published online: 16 MAY 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 7, pages 1035–1050, July 2013
How to Cite
Burkart, C., Arimoto, K.-i., Tang, T., Cong, X., Xiao, N., Liu, Y.-C., Kotenko, S. V., Ellies, L. G. and Zhang, D.-E. (2013), Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10. EMBO Mol Med, 5: 1035–1050. doi: 10.1002/emmm.201201864
- Issue published online: 3 JUL 2013
- Article first published online: 16 MAY 2013
- Manuscript Accepted: 5 APR 2013
- Manuscript Revised: 4 APR 2013
- Manuscript Received: 24 AUG 2012
- National Institutes of Health. Grant Number: HL091549 to DEZ
- breast cancer;
The theory of cancer immunoediting refers to mechanisms by which the immune system can suppress or promote tumour progression. A major challenge for the development of novel cancer immunotherapies is to find ways to exploit the immune system's antitumour activity while concomitantly reducing its protumour activity. Using the PyVmT model of mammary tumourigenesis, we show that lack of the Usp18 gene significantly inhibits tumour growth by creating a tumour-suppressive microenvironment. Generation of this antitumour environment is driven by elevated secretion of the potent T-cell chemoattractant Cxcl10 by Usp18 deficient mammary epithelial cells (MECs), which leads to recruitment of Th1 subtype CD4+ T cells. Furthermore, we show that Cxcl10 upregulation in MECs is promoted by interferon-λ and that Usp18 is a novel inhibitor of interferon-λ signalling. Knockdown of the interferon-λ specific receptor subunit IL-28R1 in Usp18 deficient MECs dramatically enhances tumour growth. Taken together, our data suggest that targeting Usp18 may be a viable approach to boost antitumour immunity while suppressing the protumour activity of the immune system.