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Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN‐λ and elevated secretion of Cxcl10
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Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN‐λ and elevated secretion of Cxcl10
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Journal Article
Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN‐λ and elevated secretion of Cxcl10
2013
Overview
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.
Graphical Abstract
Usp18 regulates the mammary tumor microenvironment via IFN‐λ signalling in epithelial cells: secreted Cxcl10 attract Th1 cells that will block tumor growth. These findings provide new candidates for epithelial breast cancer immunotherapy.
Publisher
Nature Publishing Group UK,EMBO Press,Springer Nature
Subject
/ Animals
/ Breast Neoplasms - blood supply
/ Breast Neoplasms - immunology
/ Breast Neoplasms - pathology
/ CD4-Positive T-Lymphocytes - immunology
/ Chemokine CXCL10 - immunology
/ Cxcl10
/ Epithelial Cells - immunology
/ Epithelial Cells - metabolism
/ Epithelial Cells - pathology
/ Female
/ Gene Expression Regulation, Neoplastic
/ Hypersensitivity - immunology
/ Interferon-gamma - immunology
/ Mice
/ Neovascularization, Pathologic - genetics
/ Neovascularization, Pathologic - immunology
/ Neovascularization, Pathologic - pathology
/ Rodents
/ Tumors
/ UBP43
/ Usp18
