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IFNL4-ΔG Allele Is Associated with an Interferon Signature in Tumors And Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IFNL4-G allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer Wei Tang1, Tiffany A. Wallace1, Ming Yi2, Cristina Magi-Galluzzi3, Tiffany H. Dorsey1, Olusegun O. Onabajo4, Adeola Obajemu4, Symone V. Jordan1, Christopher A. Loffredo5, Robert M. Stephens2, Robert H. Silverman6, George R. Stark6, Eric A. Klein7, Ludmila Prokunina-Olsson4, and Stefan Ambs1 1 Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA 2 Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA 3 Department of Pathology, Cleveland Clinic, Cleveland, OH, USA 4 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, MD, USA 5 Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 6 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA 7 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA Running title: Interferon signature and African-American prostate cancer patients Key words: Prostate cancer, IFNL4, interferon signature, African-American, gene expression, disease recurrence, immune therapy, IDO1 Abbreviations: AA, African-American; EA, European-American; IFNL4, interferon-4; IRDS, interferon-related DNA damage resistance signature; IRG, interferon response genes; ISG, interferon-stimulated gene; IDO1, indoleamine-2,3-dioxygenase-1 Address all correspondence to: Stefan Ambs, PhD, Laboratory of Human Carcinogenesis, NCI, NIH, Bldg.37/Room 3050B, Bethesda, MD 20892-4258. Phone 240-760-6836; Email: [email protected] Conflict of interest: The authors declare no potential conflicts of interest. 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. TRANSLATIONAL RELEVANCE 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 in prostate tumors that has a high prevalence in African-American patients. This signature, known as “Interferon-related DNA Damage Resistance Signature” (IRDS), predicts decreased disease-free survival. Moreover, we link its occurrence to a germline variant allele, rs368234815-G, within the interferon λ4 (IFNL4) gene. This IFNL4 allele controls production of a type-III interferon, IFN-λ4, and is a known predictor of decreased viral clearance. Together, these 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. 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT 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 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, 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 in three human prostate cancer cell lines. Conclusions: Our study links a germline variant that controls production of IFN-λ4 to the occurrence of a clinically relevant interferon signature in prostate tumors that may predominantly affect men of African ancestry. 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Prostate cancer incidence and mortality rates are highest among men of African ancestry (1-3). Environmental exposures and ancestry-specific factors may influence prostate cancer biology and cause a more aggressive disease in these men (4-11). We and others described an immune signature that is prevalent in prostate tumors of African-American (AA) patients and hypothesized that this signature affects tumor biology (5, 12-15). Here, we further investigated this immune signature and discovered an interferon signature in tumors of AA patients that is analogous to the previously described interferon-related DNA damage resistance signature, also termed IRDS (16). IRDS includes 49 interferon-stimulated genes (ISGs) that are induced through activation of the JAK-STAT pathway (17). IRDS was initially identified because of its effects leading to resistance to ionizing radiation. It can be induced by persistent activation of the JAK-STAT pathway by various exogenous and endogenous stimuli that generate an interferon response (18, 19). All interferons (type-I, type-II, type-III) induce sets of ISGs that are overlapping but also distinct. However, among the human interferons, the expression of the recently discovered IFN- λ4, a type-III interferon, is uniquely controlled by genetics. Only carriers of the G allele for the germline variant rs368234815-ΔG/TT in the IFNL4 gene can produce this interferon (20). This allele is most common in individual of African ancestry (up to 80% allele frequency), while it is less common in Europeans (~30%) and Asians (less than 10%) (20). Moreover, carriers of IFNL4 rs368234815-ΔG have an impaired ability to clear certain viral infections, such as hepatitis C virus (HCV), spontaneously or after treatment (20). One of the mechanisms by which IFN-λ4 renders cells refractory to an antiviral response is the induction of a persistent gene signature 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. that resembles IRDS (20, 21). Thus, we hypothesized that because IFN-λ4 is produced more commonly in men of African ancestry, it might explain the increased occurrence of IRDS in their tumors, and be of clinical importance. Accordingly, we examined whether IFNL4 rs368234815- ΔG is associated with the development of IRDS in prostate tumors and disease outcomes. Consistent with our hypothesis, we found that IFNL4 rs368234815-ΔG is significantly associated with both the presence of IRDS and an increased all-cause mortality among AA prostatectomy patients. 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. MATERIALS AND METHODS Study design, patient data, and cell lines. To compare gene expression profiles from prostate tumors of AA and EA patients, we analyzed gene expression data from two patient cohorts that were previously described in detail by us (12) and others (22). These two datasets are publicly available (GSE6956, GSE21032) and consist of microarray data for primary prostate tumors from 33 AA and 36 EA men (12) and 24 AA (non-Hispanic) and 98 EA men (22). These men were previously untreated prostatectomy patients with exception of 16 patients in the Taylor et al. cohort who received neoadjuvant hormone therapy or chemotherapy. We examined the prevalence of two previously reported interferon-related
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