Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance

• Published in: Cell reports (Cambridge) Vol. 16; no. 9; pp. 2348 - 2358
• Main Authors: Saddawi-Konefka, Robert, Seelige, Ruth, Gross, Emilie T.E., Levy, Eric, Searles, Stephen C., Washington, Allen, Santosa, Endi K., Liu, Beichen, O’Sullivan, Timothy E., Harismendy, Olivier, Bui, Jack D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-08-2016; Elsevier
• Subjects: Animals; Carcinogens; Cell Line, Tumor; Cercopithecus aethiops; Gene Expression Regulation; Humans; Immunologic Surveillance; immunosurveillance; innate immunity; Interleukin-17 - genetics; Interleukin-17 - immunology; interleukin-17D; Methylcholanthrene; Mice; Mice, Inbred C57BL; Mice, Knockout; Muromegalovirus - growth & development; Muromegalovirus - immunology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - immunology; NK cells; Nrf2; Sarcoma - chemically induced; Sarcoma - genetics; Sarcoma - immunology; Sarcoma - pathology; Signal Transduction; Soft Tissue Neoplasms - chemically induced; Soft Tissue Neoplasms - genetics; Soft Tissue Neoplasms - immunology; Soft Tissue Neoplasms - pathology; tumor rejection; Vaccinia virus - growth & development; Vaccinia virus - immunology; Vero Cells; NK cells; innate immunity; Nrf2; immunosurveillance; interleukin-17D; tumor rejection
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.07.075

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.
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•The transcription factor Nrf2 induces the cytokine IL-17D•IL-17D is required for effective antitumor and antiviral immune responses•Induction of Nrf2 by agonists in established tumors can lead to tumor regression•IL-17D-mediated tumor regression requires Nrf2 expression in tumors
Saddawi-Konefka et al. show that the transcription factor nuclear factor erythroid-derived 2-like 2, or Nrf2, induces the cytokine interleukin-17D. Nrf2/IL-17D-mediated natural killer cell recruitment can lead to the regression of established tumors. Therefore, inducing IL-17D using Nrf2 agonists has potential for cancer immune therapy.