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.

Investigations of Interferon-Lambda for the Treatment of Cancer

“…The potential for IFN-λ's influence on the balance between Th1 and Th2 immune responses to impact cancer was recently highlighted by an investigation of the IFN-inducible gene USP18 in a mouse model of spontaneous breast cancer by Burkart et al [43]. USP18 is known to be a negative regulator of type I IFN responses, and USP18 deficiency has been reported to have an inhibitory effect on the development of leukemia.…”

“…To investigate this, Burkart et al [43] analyzed the expression of T cell-specific chemokines and found that the Cxcr3 ligands Cxcl10 and Cxcl11 were significantly upregulated in PyVmT/USP18 KO tumors. Since expression of Cxcr3 is associated with Th1 cells, the authors investigated if PyVmT/USP18 KO tumors showed a Th1 cytokine profile and found they had increased expression of IFN-γ and decreased expression of the Th2 cytokines IL-4 and IL-13.…”

IFN-λ Cancer Immunotherapy: New Kid on the Block

“…The authors reported a role for NK cells, T cells and neutrophils in mediating the antitumor activity of IFN-λ. We and other groups have also validated the antitumor role of IFN-λ in other tumor models, including lung [77], hepatoma [78], esophagus [79,80], breast c ancer [81], prostate [82] and colon cancer [83].…”

“…Durable antitumor immune responses have also been reported for IFN-λ [78]. These responses have largely been associated with induction of T-cell responses, as reported in the antitumor activity of IFN-λ in melanoma [75], fibrosarcoma [76], lung adenocarcinoma [79] and breast cancer [81]. However IFN-λ-induced innate immunity, largely represented by NK-cell induction, was demonstrated in numerous cancer models, including melanoma [75], fibrosarcoma [76], hepatoma [78], lung adenocarcinoma [79] and prostate adenocarcinoma [82].…”

“…By using either a gene therapy approach or direct injection of IFN-α and IFN-λ, we have demonstrated that around 50% of mice achieve complete responses [93]. Although the use of IFN-λ as an alternative to IFN-α can be introduced in cases of resistance to IFN-α t reatment Anti-angiogenesis Melanoma [19] Anti-proliferative Melanoma [19] Lung adenocarcinoma [77] Neuroendocrine cancer [84] T lymphoma [85] Colon cancer [86] Hepatoma [87] Cell cycle arrest Melanoma [75] Colon cancer [75] Esophageal carcinoma [80] Antimitotic Melanoma [19] Apoptosis Melanoma [75] Colon cancer [75,83] Lung adenocarcinoma [77,79] Esophageal carcinoma [80] Tumor microenvironment cells Melanoma [19] NK cells Melanoma [75] Fibrosarcoma [76] Hepatoma [78] Lung adenocarcinoma [79] Prostate adenocarcinoma [82] T cells Melanoma [75] Fibrosarcoma [76] Lung adenocarcinoma [79] Breast cancer [81] Neutrophils Fibrosarcoma [76] Macrophages Fibrosarcoma [76] future science group…”