Search

Summary Background The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. Methods We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. Findings We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23–2·10; p=0·0005 in the discovery dataset; 1·22, 1·05–1·40; p=0·0072 in the validation dataset; and 1·27, 1·12–1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02–1·51; p=0·034 in the discovery dataset; 1·10, 0·98–1·20; p=0·10 in the validation dataset; and 1·11, 1·02–1·22; p=0·018 in the combined dataset. Interpretation Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. Funding The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.

IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.

Since its discovery in 2013, interferon lambda 4 (IFN-λ4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-λ4, especially in secreted form even led to questions about its existence. However, the genetic ability to generate IFN-λ4, determined by the presence of the rs368234815-ΔG allele, is the strongest predictor of impaired clearance of hepatitis C virus (HCV) infection in humans. Significant modulation of IFN-λ4 activity by a genetic variant (P70S) supports IFN-λ4, and not other type III IFNs encoded in the same genomic locus, as the primary functional cause of the association with HCV clearance. Although the ability to produce IFN-λ4 is associated with decreased HCV clearance, the recombinant IFN-λ4 is active against HCV and other viruses. These observations present an apparent conundrum—when and how does a presumably good IFN, with anti-HCV activity, interfere with the ability to clear HCV? In this review, we discuss findings that suggest potential mechanisms for explaining this conundrum.

Chronic hepatitis C virus (HCV) infection and cirrhosis are major risk factors for developing hepatocellular carcinoma (HCC). Genetic polymorphisms in theIFNL3/IFNL4locus have been associated both with impaired clearance of HCV and protection from liver fibrosis, an early stage of cirrhosis. Here, we aimed to address the genetic and functional relationships betweenIFNL3/IFNL4polymorphisms, HCV-related cirrhosis, and HCC risk. We evaluated associations betweenIFNL4genotype, defined as the presence of rs368234815-dG or rs12979860-T alleles, with cirrhosis and HCC risk in patients with chronic HCV - 2,931 from Taiwan and 3,566 from Japan. We detected associations betweenIFNL4genotype and decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwan), but increased risk of HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058, in Japan).In-vitro, IFN-λ4 expression increased ER stress, and enhanced positive regulation of IFN responses via IRF1 induction, which mediated antiproliferative effects in hepatic cells. Our data present novel IFN-λ4-associated pathways that may be contributing to HCV persistence and development of HCC.

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we analyzed episodes of malaria, gastrointestinal and respiratory infections using information for 30,626 clinic visits from birth through up to 5 years of follow-up. Genetic polymorphisms IFNL4-rs368234815 and IFNL3-rs4803217 that functionally affect type III interferons were genotyped with TaqMan assays. For both genetic variants and each infection, we evaluated time-to-first episode and calculated odds ratios (ORs) for the risk of an infection episode during follow-up, controlling for relevant covariates. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.003) and respiratory infection (p=0.045). The risk of experiencing an infection episode during the follow-up was also significantly increased with each copy of the rs368234815-dG allele – for gastrointestinal infections (OR=1.53, 95%CI (1.13-2.07), p=0.005) and malaria (OR=1.30, 95%CI (1.02-1.65), p=0.033). IFNL4-rs368234815 and IFNL3-rs4803217 were in moderate linkage disequilibrium in this population (r2=0.78), and all the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-λ4 and not IFN-λ3 as the primary cause of these associations. We conclude that the ability to produce IFN-λ4 may have broad health-related implications by negatively affecting the immune response and clinical outcomes of several common infections.

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0-15 years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (

Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American (AA) patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the IFNλ4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells. Results: We found that a distinct interferon (IFN) signature that is analogous to the previously described “IFN-related DNA damage resistance signature” (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of AA than European-American men. Furthermore, analysis in TCGA showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-ΔG) that controls production of IFNλ4, a type III IFN, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of AA patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines. Conclusions: Our study links a germline variant that controls production of IFNλ4 to the occurrence of a clinically relevant IFN signature in prostate tumors that may predominantly affect men of African ancestry. Clin Cancer Res; 24(21); 5471–81. ©2018 AACR.

Background: Genetic polymorphisms within the IFNL3 / IFNL4 genomic region, which encodes type III interferons, have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. Methods: In a cohort of 914 Malian children, we analyzed episodes of malaria, gastrointestinal and respiratory infections using information for 30,626 clinic visits from birth through 1-5 years of follow-up. Genetic polymorphisms IFNL4 -rs368234815 and IFNL3-rs4803217 that functionally affect type III interferons were genotyped with TaqMan assays. For both genetic variants and each infection, we evaluated time-to-first episode and calculated odds ratios (ORs) for the risk of an infection episode during follow-up. Results: Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.003) and respiratory infection (p=0.045). The risk of experiencing an infection episode during the follow-up was also significantly increased with each copy of the rs368234815-dG allele – for gastrointestinal infections (OR=1.53, 95%CI (1.13-2.07), p=0.005) and malaria (OR=1.30, 95%CI (1.02-1.65), p=0.033). IFNL4 -rs368234815 and IFNL3 -rs4803217 were in moderate linkage disequilibrium in this population (r2 =0.78), and all the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-λ4 and not IFN-λ3 as the primary cause of these associations. Interpretation: Our results provide support for the role of IFN-λ4 in common gastrointestinal infections, and possibly in other infections as well. Trial Registration: NCT01168271 Funding Statement: The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), the Intramural Research Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services. Declaration of Interests: L.P.-O. is a co-inventor on IFN-λ4-related patents issued to NCI/NIH, and receives royalties for monoclonal antibodies for IFN-λ4 detection. Other authors have no conflict of interest to declare. Ethics Approval Statement: The protocol and study procedures were approved by the institutional review board of the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (ClinicalTrials.gov ID NCT01168271), and the Ethics Committee of the Faculty of Medicine, Pharmacy and Dentistry at the University of Bamako, Mali.

The Viewpoint discusses the benefits and potential limitations of using interferon lambda (IFN-λ, a type III interferon) to prevent, limit, and treat COVID-19. Due to the restricted expression of its receptor complex, IFN-λ provides localized antiviral protection to epithelial cells, including in the respiratory tract., With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.

Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the interferon λ4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed IFNL4 genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells. Results: We found that a distinct interferon signature that is analogous to the previously described “Interferon-related DNA Damage Resistance Signature” (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of African-American than European-American men. Furthermore, analysis in The Cancer Genome Atlas (TCGA) showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-ΔG) that controls production of IFN-λ4 protein, a type-III interferon, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of African-American patients. Moreover, IFNL4 overexpression induced IRDS-like signatures in three human prostate cancer cell lines. Conclusions: Tumor interferon signaling has recently been shown to modulate response and resistance to immune checkpoint blockade. Here, we describe a distinct and biologically relevant interferon signature, IRDS, in prostate tumors that has a high prevalence in African-American patients. Our observations indicate that IRDS and IFNL4 rs368234815-ΔG may have a function in the tumor biology and survival of African-American patients, and influence immune therapy outcomes, which should be examined in future studies. Citation Format: Wei Tang, Tiffany Wallace, Ming Yi, Cristina Magi-Galluzzi, Tiffany Dorsey, Olusegun Onabajo, Adeola Obajemu, Symone Jordan, Christopher Loffredo, Robert Stephens, Robert Silverman, George Stark, Eric Klein, Ludmila Prokunina-Olsson, Stefan Ambs. IFNL4-deltaG allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B051.

Background: Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria. Methods: Serum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression. Findings: There was stronger reactivity to the severe malaria associated CIDRα1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p = 0·001; Uganda: p = 0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24–0·63; pheterogeneity = 0·00011) and Uganda (aOR 0·60, 95% CI 0.41–0·88; pheterogeneity = 0·008). eBL was inversely associated with reactivity, coded as quartiles, to group A variant CIDRδ1 (ptrend = 0·035) in Ghana and group B CD36-binding variants CIDRα2·2 (ptrend = 0·006) and CIDRα2·4 (ptrend = 0·033) in Uganda, and positively associated with reactivity to SERA5 in Ghana (ptrend = 0·017) and Uganda (ptrend = 0·007) and group A CIDRα1·5 variant in Uganda only (ptrend = 0·034). Interpretation: eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk. Funding: Intramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.

Sexually transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. Humans are polymorphic for the germline dinucleotide variant, rs368234815-TT/ΔG, in the IFNL4 gene encoding interferon λ4. Since the IFNL4-ΔG allele has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of lifetime sexual partners, may increase prostate cancer risk in an IFNL4-ΔG-dependent manner. Accordingly, we find that men with 10 or more sexual partners and at least one copy of IFNL4-ΔG have a significantly increased risk of prostate cancer while those with the same number of partners but lacking IFNL4-ΔG do not. Moreover, a test for effect modification shows a positive interaction between the number of lifetime partners and IFNL4-ΔG in the development of aggressive prostate cancer. Based on these findings, we conclude that a gene–environment interaction between IFNL4-ΔG and sexual activity may increase the risk of prostate cancer., Tsion Zewdu Minas et al. find that men carrying an IFNL4 variant that is more common in African Americans and is associated with impaired viral clearance have a higher risk of prostate cancer. Specifically, this risk is increased in IFNL4 variant carriers with more lifetime sexual partners, suggesting a link to impaired clearance of sexually transmitted infections

Introduction. Interferon Lambda 4 gene (IFNL4) encodes IFN-λ4 protein, a new member of the type-III interferon family. IFNL4 genotype (rs368234815-dG allele), defines the genetic ability to produce IFN-λ4 and has been associated with reduced clearance of hepatitis C virus (HCV) infection. Given antiviral activity and immune modulation properties of IFN-λ4, we hypothesized that IFNL4 genotype of recipient and/or donor may modulate post-transplant survival outcomes, possibly through control of viral infections, and/or alloreactivity. Methods. From the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we randomly selected 627 patients who received unrelated hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML, N=449) or acute lymphocytic leukemia (ALL, N=178). The patients had to match the following criteria: 1) HCT between 2004 and 2012, 2) available pre-HCT blood sample for the donor and recipient, 3) 8/8 HLA matching, and 3) myeloablative conditioning. IFNL4 genotyping was completed for 619 donors and 522 recipients using a custom-designed TaqMan assay for rs368234815. Multivariable Cox proportional hazard models were used for statistical analyses. Follow-up ended in November 2017. Results. Median age at HCT was 40 years (range=0.05 for OS, DFS, and TRM) Conclusions. Donor IFNL4 genotype is associated with risk of transplant-related mortality in patients with acute leukemia. The data suggest that avoiding donors with dG/dG genotype will improve HCT outcomes without limiting the potential donor pool. A validation study is needed; if confirmed, IFNL4 genotype may provide an added value to donor selection criteria. Disclosures Lee: Onyx: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Takeda: Research Funding.

Antigen-specific tolerance induction using autologous B-cell gene therapy is a potential treatment to eliminate undesirable immune responses. For example, we have shown that experimental autoimmune encephalomyelitis (EAE) and type 1 diabetes in NOD mice can be ameliorated using antigen-Ig fusion protein transduced B cells. However, it is well established that auto-reactive antigen-specific B cells are activated in many autoimmune diseases and can contribute to pathogenesis. While syngeneic B cells from immunized or autoimmune mice can serve as tolerogenic antigen-presenting cells (APC), this observation begs the question of whether the antigen-specific B cells per se can be transduced as tolerogenic APC. To test this, we employed two model systems employing B cell receptor (BCR) transgenic or wild type (wt) mice as B-cell donors. While adoptively transferred MOG-Ig transduced wt C57Bl/6 B cells were highly tolerogenic and ameliorated EAE, MOG-Ig transduced anti-MOG B cells from BCR transgenic mice were not. This phenomenon was reproduced in the NOD diabetes model in which pro-insulin-Ig transduced polyclonal wt NOD B cells were protective, whereas similarly transduced anti-insulin BCR B cells were not. Since the frequency of antigen-specific B cells in an immunized animal is quite low, we wished to determine the threshold numbers of BCR transgenic B cells that could be present in an effective transduced population. Therefore, we "spiked" polyclonal wt C57Bl/6 B cells with different numbers of anti-MOG BCR transgenic B cells. In the EAE model, we found protection when BCR B cells were present at 1%, but they prevented tolerance induction at 10%. Antigen-specific B cells expressed normal levels of co-stimulatory molecules and were tolerogenic when transduced with an irrelevant antigen (OVA). Thus, the presence of a BCR specific for the target autoantigen may interfere with the tolerogenic process to that antigen, but BCR-specific B cells are not intrinsically defective as tolerogenic APC. Taken together, these data suggest that antigen-specific tolerance induction can be achieved in the presence of a limited number of antigen-specific B cells, but higher numbers of pathogenic B cells may mask this induction. This observation should guide future development of therapies using autologous B cells to treat patients with autoimmune diseases.