Type I Interferon in Chronic Virus Infection and Cancer

Overview

Journal Trends Immunol

Specialty Allergy & Immunology

Date 2017 Jun 6

PMID 28579323

Citations 255

Authors

Laura M Snell

Tracy L McGaha

David G Brooks

Affiliations

Soon will be listed here.

Abstract

Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN-I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases.

Citing Articles

Aberrant DNA methylation of genes regulating CD4+ T cell HIV-1 reservoir in women with HIV.

Xu K, Zhang X, Asam K, Quach B, Page G, Konkle-Parker D Clin Transl Med. 2025; 15(3):e70267.

PMID: 40070009 PMC: 11896887. DOI: 10.1002/ctm2.70267.

Engineering non-pathogenic bacteria for auto-transporter-driven secretion of functional interferon.

Tfilin Samuel M, Rostovsky I, Kuzmina A, Taube R, Sal-Man N Gut Microbes. 2025; 17(1):2474146.

PMID: 40032826 PMC: 11881866. DOI: 10.1080/19490976.2025.2474146.

The Role of Sustained Type I Interferon Secretion in Chronic HIV Pathogenicity: Implications for Viral Persistence, Immune Activation, and Immunometabolism.

Teer E, Mukonowenzou N, Essop M Viruses. 2025; 17(2).

PMID: 40006894 PMC: 11860620. DOI: 10.3390/v17020139.

Gene regulatory logic of the interferon-β enhancer contains multiple selectively deployed modes of transcription factor synergy.

Schiffman A, Cheng Z, Ourthiague D, Hoffmann A bioRxiv. 2025; .

PMID: 39975349 PMC: 11838565. DOI: 10.1101/2025.02.04.636520.

m5C methylation modification may be an accomplice in colorectal cancer escaping from anti-tumor effects of innate immunity-type I/III interferon.

Sun Y, Liu Y, Jiang L, Zhong C Front Immunol. 2025; 15:1512353.

PMID: 39867908 PMC: 11757137. DOI: 10.3389/fimmu.2024.1512353.

References

Levin D, Schneider W, Hoffmann H, Yarden G, Busetto A, Manor O . Multifaceted activities of type I interferon are revealed by a receptor antagonist. Sci Signal. 2014; 7(327):ra50. PMC: 4311876. DOI: 10.1126/scisignal.2004998. View

Gonzalez-Navajas J, Lee J, David M, Raz E . Immunomodulatory functions of type I interferons. Nat Rev Immunol. 2012; 12(2):125-35. PMC: 3727154. DOI: 10.1038/nri3133. View

Penaloza-MacMaster P, Kamphorst A, Wieland A, Araki K, Iyer S, West E . Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med. 2014; 211(9):1905-18. PMC: 4144726. DOI: 10.1084/jem.20132577. View

Heim M . 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nat Rev Immunol. 2013; 13(7):535-42. DOI: 10.1038/nri3463. View

Katlinski K, Gui J, Katlinskaya Y, Ortiz A, Chakraborty R, Bhattacharya S . Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. Cancer Cell. 2017; 31(2):194-207. PMC: 5313042. DOI: 10.1016/j.ccell.2017.01.004. View

Fenton-May A, Dibben O, Emmerich T, Ding H, Pfafferott K, Aasa-Chapman M . Relative resistance of HIV-1 founder viruses to control by interferon-alpha. Retrovirology. 2013; 10:146. PMC: 3907080. DOI: 10.1186/1742-4690-10-146. View

Munn D, Mellor A . IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 2016; 37(3):193-207. PMC: 4916957. DOI: 10.1016/j.it.2016.01.002. View

Lee M, Park C, Jeong Y, Kim Y, Ha S . Negative regulation of type I IFN expression by OASL1 permits chronic viral infection and CD8⁺ T-cell exhaustion. PLoS Pathog. 2013; 9(7):e1003478. PMC: 3715418. DOI: 10.1371/journal.ppat.1003478. View

Osterborg A, Bjorkholm M, Bjoreman M, Brenning G, Carlson K, Celsing F . Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood. 1993; 81(6):1428-34. View

10.

Corrales L, Glickman L, McWhirter S, Kanne D, Sivick K, Katibah G . Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015; 11(7):1018-30. PMC: 4440852. DOI: 10.1016/j.celrep.2015.04.031. View

11.

Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau J, Maloisel F . Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997; 337(4):223-9. DOI: 10.1056/NEJM199707243370402. View

12.

Chen L, Borozan I, Feld J, Sun J, Tannis L, Coltescu C . Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology. 2005; 128(5):1437-44. DOI: 10.1053/j.gastro.2005.01.059. View

13.

Getts D, Turley D, Smith C, Harp C, McCarthy D, Feeney E . Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol. 2011; 187(5):2405-17. PMC: 3159828. DOI: 10.4049/jimmunol.1004175. View

14.

Sangfelt O, Erickson S, Castro J, Heiden T, Gustafsson A, EINHORN S . Molecular mechanisms underlying interferon-alpha-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins. Oncogene. 1999; 18(18):2798-810. DOI: 10.1038/sj.onc.1202609. View

15.

de Weerd N, Vivian J, Nguyen T, Mangan N, Gould J, Braniff S . Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nat Immunol. 2013; 14(9):901-7. DOI: 10.1038/ni.2667. View

16.

Purtha W, Chachu K, Virgin 4th H, Diamond M . Early B-cell activation after West Nile virus infection requires alpha/beta interferon but not antigen receptor signaling. J Virol. 2008; 82(22):10964-74. PMC: 2573246. DOI: 10.1128/JVI.01646-08. View

17.

Wonderlich E, Barratt-Boyes S . SIV infection of rhesus macaques differentially impacts mononuclear phagocyte responses to virus-derived TLR agonists. J Med Primatol. 2013; 42(5):247-53. PMC: 3777745. DOI: 10.1111/jmp.12064. View

18.

Bidwell B, Slaney C, Withana N, Forster S, Cao Y, Loi S . Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat Med. 2012; 18(8):1224-31. DOI: 10.1038/nm.2830. View

19.

Vicari A, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F . Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med. 2002; 196(4):541-9. PMC: 2196048. DOI: 10.1084/jem.20020732. View

20.

Yamada T, Horimoto H, Kameyama T, Hayakawa S, Yamato H, Dazai M . Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. Nat Immunol. 2016; 17(6):687-94. DOI: 10.1038/ni.3422. View