title: Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10.
abstract: 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.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Burkart
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Arimoto
authors.forename: Tingdong
authors.initials: T
authors.lastname: Tang
authors.forename: Xiuli
authors.initials: X
authors.lastname: Cong
authors.forename: Nengming
authors.initials: N
authors.lastname: Xiao
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001940:Breast / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology*; D010450:Endopeptidases / Q000235:genetics*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D043222:Ubiquitin Thiolesterase; D015854:Up-Regulation
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D007371:Interferon-gamma; D010450:Endopeptidases; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase
keywords: Cxcl10; UBP43; Usp18; breast cancer; interferon-λ