University of Oulu

Jouni Härkönen, Petri Pölönen, Ashik Jawahar Deen, Ilakya Selvarajan, Hanna-Riikka Teppo, Elitsa Y. Dimova, Thomas Kietzmann, Maarit Ahtiainen, Juha P. Väyrynen, Sara A. Väyrynen, Hanna Elomaa, Niko Tynkkynen, Tiia Eklund, Teijo Kuopio, Eva-Maria Talvitie, Pekka Taimen, Markku Kallajoki, Minna U. Kaikkonen, Merja Heinäniemi, Anna-Liisa Levonen, A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies, Redox Biology, Volume 61, 2023, 102644, ISSN 2213-2317,

A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies

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Author: Härkönen, Jouni1,2; Pölönen, Petri1,3; Deen, Ashik Jawahar1;
Organizations: 1Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland
2Department of Pathology, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland
3Faculty of Health Sciences, Institute of Biomedicine, University of Eastern Finland, Kuopio, 70210, Finland
4Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, 90220, Finland
5Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, 90570, Finland
6Department of Pathology, Oulu University Hospital, Oulu, 90220, Finland
7Faculty of Biochemistry and Molecular Medicine, University of Oulu and Biocenter Oulu, Oulu, 90570, Finland
8Department of Education and Research, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland
9Department of Internal Medicine, Oulu University Hospital, Oulu, 90220, Finland
10Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland
11Gerontology Research Center (GEREC), Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, 40014, Finland
12Department of Genomics, Turku University Hospital and University of Turku, Turku, 20520, Finland
13Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku, 20520, Finland
14Department of Pathology, Turku University Hospital, Turku, 20521, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 11.5 MB)
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Language: English
Published: Elsevier, 2023
Publish Date: 2023-10-02


The NRF2 pathway is frequently activated in various cancer types, yet a comprehensive analysis of its effects across different malignancies is currently lacking. We developed a NRF2 activity metric and utilized it to conduct a pan-cancer analysis of oncogenic NRF2 signaling. We identified an immunoevasive phenotype where high NRF2 activity is associated with low interferon-gamma (IFNγ), HLA-I expression and T cell and macrophage infiltration in squamous malignancies of the lung, head and neck area, cervix and esophagus. Squamous NRF2 overactive tumors comprise a molecular phenotype with SOX2/TP63 amplification, TP53 mutation and CDKN2A loss. These immune cold NRF2 hyperactive diseases are associated with upregulation of immunomodulatory NAMPT, WNT5A, SPP1, SLC7A11, SLC2A1 and PD-L1. Based on our functional genomics analyses, these genes represent candidate NRF2 targets, suggesting direct modulation of the tumor immune milieu. Single-cell mRNA data shows that cancer cells of this subtype exhibit decreased expression of IFNγ responsive ligands, and increased expression of immunosuppressive ligands NAMPT, SPP1 and WNT5A that mediate signaling in intercellular crosstalk. In addition, we discovered that the negative relationship of NRF2 and immune cells are explained by stromal populations of lung squamous cell carcinoma, and this effect spans multiple squamous malignancies based on our molecular subtyping and deconvolution data.

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Series: Redox biology
ISSN: 2213-2317
ISSN-E: 2213-2317
ISSN-L: 2213-2317
Volume: 61
Article number: 102644
DOI: 10.1016/j.redox.2023.102644
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This study was supported by University of Eastern Finland Doctoral Program in Molecular Medicine, Finnish Cancer Foundation, The Academy of Finland (Grant number 332697), Sigrid Juselius Foundation, Paavo Koistinen Foundation (AL.L. lab) and Aatos Erkko Foundation (Grant number 210013) (T.K. lab). The study benefited from samples from Auria Biopankki Turku, Finland, and Central Finland Biobank, Jyväskylä, Finland.
Copyright information: © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (