title: Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.
abstract: Cells undergoing xenobiotic or oxidative stress activate the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2), which initiates an intrinsic "stress surveillance" pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d(-/-) mice experienced a higher incidence of tumors and exacerbated viral infections compared to wild-type (WT) animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection.
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Saddawi-Konefka
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Seelige
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Emilie T E
authors.initials: ET
authors.lastname: Gross
authors.affiliation: Moores Cancer Center Oncogenomics Laboratory, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Levy
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Searles
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Washington
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Endi K
authors.initials: EK
authors.lastname: Santosa
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Beichen
authors.initials: B
authors.lastname: Liu
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: O'Sullivan
authors.affiliation: Moores Cancer Center Oncogenomics Laboratory, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Harismendy
authors.affiliation: Department of Pathology, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: jbui@ucsd.edu.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
mesh_terms: D000818:Animals; D002273:Carcinogens; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D007157:Immunologic Surveillance; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000254:growth & development / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology*; D012509:Sarcoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014616:Vaccinia virus / Q000254:growth & development / Q000276:immunology; D014709:Vero Cells
chemical_list: D002273:Carcinogens; C464462:IL17D protein, human; D020381:Interleukin-17; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D008748:Methylcholanthrene
keywords: NK cells; Nrf2; immunosurveillance; innate immunity; interleukin-17D; tumor rejection