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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.

Background Type III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-λs are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. Methods TaqMan allele discrimination assays were used to determine IFNL3/4 SNP genotypes of 1620 healthy controls and 1013 SLE patients (two independent cohorts consisting of 831 and 182 subjects, respectively) from Taiwan. The distributions of IFNL3/4 SNP genotypes and allele frequencies were compared between SLE patients and healthy controls and among SLE patients stratified by clinical phenotypes. ELISA was used to determine the serum IFN-λ3 concentrations of SLE patients. Results All major IFN3/4 SNP alleles were significantly associated with the risk for lupus nephritis (rs8099917T, P FDR  = 0.0021, OR 1.75, 95% CI 1.24–2.47; rs12979860C, P FDR  = 0.0034, OR 1.65, 95% CI 1.18–2.30; rs4803217C, P FDR  = 0.0021, OR 1.76, 95% CI 1.25–2.48; and ss469415590TT, P FDR  = 0.0021, OR 1.73, 95% CI 1.23–2.42) among SLE patients. Similarly, the major IFNL3/4 SNP haplotype rs8099917T-ss469415590TT-rs12979860C-rs4803217C (or T-TT-C-C) was a significant risk factor for lupus nephritis ( P  = 0.0015, OR 1.68, 95% CI 1.22–2.32). Additionally, all minor IFN3/4 SNP alleles were significantly associated with SLE susceptibility in nephritis-negative SLE patients as compared to normal healthy controls (rs8099917G, P FDR  = 0.00177, OR 1.68, 95% CI 1.24–2.28; rs12979860T, P FDR  = 0.00299, OR 1.58, 95% CI 1.18–2.32; rs4803217A, P FDR  = 0.00176, OR 1.65, 95% CI 1.22–2.23; and ss469415590ΔG, P FDR  = 0.00176, OR 1.70, 95% CI 1.26–2.29). Furthermore, the elevated serum levels of IFN-λ3 were significantly correlated with the complement depression and the high SLE disease activities in SLE patients. Conclusions IFN-λ3/4 genetic variants play a unique role in the development of lupus nephritis and SLE.

Background. Feedback mechanisms between interferons α and λ (IFNs) may be affected by single nucleotide polymorphisms (SNP) in interleukin 28B (IL-28B; IFN-λ3) promoter region and may influence cytomegalovirus (CMV) replication. Methods. We associated IL-28B SNPs with the risk of CMV replication after transplantation. Next, we examined the effect of IL-28B genotypes on IL-28B, and IFN-stimulated gene (ISG) expression, and CMV replication in human foreskin fibroblast (HFF) and peripheral blood mononuclear cells (PBMCs). Results. Transplant recipients with an IL-28B SNP (rs8099917) had significantly less CMV replication (P = .036). Both HFF-cells and PBMCs with a SNP showed lower IL-28B expression during infection with CMV, but higher \"antiviral\" ISG expression (eg, OAS1). Fibroblasts with a SNP had a 3-log reduction of CMV replication at day 4 (P = .004). IL-28B pretreatment induced ISG expression in noninfected fibroblasts, but a relative decrease of ISG expression could be observed in CMV-infected fibroblasts. The inhibitory effects of IL-28B could be abolished by siRNA or antagonistic peptides against the IL-28 receptor. In fibroblasts, inhibition of IL-28 signaling resulted in an increase of ISG expression and 3-log reduction of CMV-replication (P = .01). Conclusions. We postulate that IL-28B may act as a key regulator of ISG expression during primary CMV infection. IL-28B SNPs may be associated with higher antiviral ISG expression, which results in better replication control.

Purpose of Review Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis, with no FDA-approved therapy. Progress in the development of effective HDV treatments is accelerating. This review highlights how mathematical modeling is improving understanding of HDV-HBsAg-host dynamics during antiviral therapy and generating insights into the efficacy and modes of action (MOA) of new antiviral agents. Recent Findings Clinical trials with pegylated-interferon-λ, bulevertide, nucleic acid polymers, and/or lonafarnib against various steps of the HDV-life cycle have revealed new viral-kinetic patterns that were not observed under standard treatment with pegylated-interferon-α. Modeling indicated that the half-lives of circulating HDV and HBsAg are ~ 1.7 d and ~ 1.3 d, respectively, estimated the relative response of HDV and HBsAg during different antiviral therapies, and provided insights into the efficacy and MOA of drugs in development for treating HDV, which can inform response-guided therapy to individualize treatment duration. Summary Mathematical modeling of HDV and HBsAg kinetics provides a window into the HDV virus lifecycle, HDV-HBsAg-host dynamics during antiviral therapy, and the MOA of new drugs for HDV.

Recent genome‐wide association studies suggest distinct roles for 12 human interferon‐alpha (IFN‐α) and 3 IFN‐λ subtypes that may be elucidated by defining the expression patterns of these sets of genes. To overcome the impediment of high homology among each of the sets, we designed a quantitative real‐time PCR assay that incorporates the use of molecular beacon and locked nucleic acid (LNA) probes, and in some instances, LNA oligonucleotide inhibitors. We then measured IFN subtype expression by human peripheral blood mononuclear cells and by purified monocytes, myeloid dendritic cells (mDC), plasmacytoid dendritic cells (pDC), and monocyte‐derived macrophages (MDM), and –dendritic cells (MDDC) in response to poly I:C, lipopolysaccharide (LPS), imiquimod and CpG oligonucleotides. We found that in response to poly I:C and LPS, monocytes, MDM and MDDC express a subtype pattern restricted primarily to IFN‐β and IFN‐λ1. In addition, while CpG elicited expression of all type I IFN subtypes by pDC, imiquimod did not. Furthermore, MDM and mDC highly express IFN‐λ, and the subtypes of IFN‐λ are expressed hierarchically in the order IFN‐λ1 followed by IFN‐λ2, and then IFN‐λ3. These data support a model of coordinated cell‐ and ligand‐specific expression of types I and III IFN. Defining IFN subtype expression profiles in a variety of contexts may elucidate specific roles for IFN subtypes as protective, therapeutic or pathogenic mediators.

[...]IFNs play critical roles in protecting the host from pathogens, controlling cellular transformation, and when dysregulated, promoting autoimmunity. Since the seminal discovery of Type I IFNs over 60 years ago (1), the Type I and Type III IFN family has grown to include 20 distinct members consisting of 16 Type I IFNs (12 IFNαs, IFNβ, IFNε, IFNκ, and IFNω) and four Type III IFNs (IFNλ1-IFNλ4) (2) that signal through common type-I (IFNAR1/IFNAR2) and type-III IFNλR1/IL10R2 receptor complexes. [...]Yang and Liprovide a detailed review of the complex anti-viral defense mechanisms used by a small set of ISGs to inhibit viral RNA replication. Two articles focus on functional differences among different type I IFN subtypes.Fox et al.provide an extensive review highlighting differences among IFNα and IFNβ subtypes in murine infectious disease models, with potential insights for human disease.Wittling et al.review human type I IFNs to propose that regulatory elements, expression patterns, and primate evolution can serve as a guide toward revealing unique roles for the IFNα subtypes.

Rabies, caused by rabies virus (RABV), is a fatal neurological disease that still causes more than 59,000 human deaths each year. Type III interferon IFN-λs are cytokines with type I IFN-like antiviral activities. Although IFN-λ can restrict the infection for some viruses, especially intestinal viruses, the inhibitory effect against RABV infection remains undefined. In this study, the function of type III IFN against RABV infection was investigated. Initially, we found that IFN-λ2 and IFN-λ3 could inhibit RABV replication in cells. To characterize the role of IFN-λ in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-λ2 or IFN-λ3, termed as rB2c-IFNλ2 or rB2c-IFNλ3, respectively, were constructed and rescued. It was found that expression of IFN-λ could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-λ could induce the activation of the JAK-STAT pathway, resulting in the production of interferon-stimulated genes (ISGs). It was also found that rRABVs expressing IFN-λ could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. Consistently, IFN-λ was found to maintain the integrity of tight junction (TJ) protein ZO-1 of BBB to alleviate neuroinflammation in a transwell model. Our study underscores the role of IFN-λ in inhibiting RABV infection, which potentiates IFN-λ as a possible therapeutic agent for the treatment of RABV infection.

Type III interferons (IFNs), or IFN-λ, are known to have potent antiviral and antiproliferative activities. It inhibits viral replication and upregulates cytotoxic responses to virally infected cells. Besides these characteristics, IFN-λ also has additional activities in the immune system. In fact, it induces the proliferation of Foxp3-expressing regulatory T cells mediated in part by dendritic cells and inhibit the production of IL-5 and IL-13 in vitro. Regulatory T cells and the Th2 cytokines like IL-5 and IL-13 play important roles in the pathogenesis of allergic asthma. In humans, there seems to be an inverse link between IFN-λ and the severity of allergic asthma and allergic asthma exacerbations. Asthmatic patients, without a detectable viral infection show an inverse correlation between IL-28 and IL-29 mRNA levels and severity of allergic responses in the airways. These additional features of IFN-λ that affect the adaptive immune system make it a potential immunotherapeutic agent for the treatment of allergic asthma.

Previous work showed that interferon-λ (IFN-λ) can trigger the synthesis of thymic stromal lymphopoietin (TSLP) by specialized epithelial cells in the upper airways of mice, thereby improving the performance of intranasally administered influenza vaccines. Here we demonstrate that protein-only influenza vaccines containing either IFN-λ or TSLP boosted antigen-specific IgG1 and IgA responses and enhanced the resistance of mice to influenza virus challenge, irrespective of whether the vaccines were applied via the intranasal or the rectal route. TSLP receptor deficiency negatively influenced vaccine-induced antiviral immunity by impairing the migration of dendritic cells from the airways to the draining lymph nodes of immunized mice, thereby restraining follicular helper T cell and germinal center B cell responses. As previously observed during intranasal vaccination, the adjuvant effect of IFN-λ on a rectally administered influenza vaccine was no longer observed when TSLP receptor-deficient mice were used for immunization, highlighting the central role of the IFN-λ/TSLP axis for vaccine-induced antiviral immunity in the mucosa.