A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies
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
Affiliations
Jouni Härkönen
Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland; Department of Pathology, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland
Petri Pölönen
Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland; Faculty of Health Sciences, Institute of Biomedicine, University of Eastern Finland, Kuopio, 70210, Finland
Ashik Jawahar Deen
Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland
Ilakya Selvarajan
Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland
Hanna-Riikka Teppo
Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, 90220, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, 90570, Finland; Department of Pathology, Oulu University Hospital, Oulu, 90220, Finland
Elitsa Y. Dimova
Faculty of Biochemistry and Molecular Medicine, University of Oulu and Biocenter Oulu, Oulu, 90570, Finland
Thomas Kietzmann
Faculty of Biochemistry and Molecular Medicine, University of Oulu and Biocenter Oulu, Oulu, 90570, Finland
Maarit Ahtiainen
Department of Education and Research, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland
Juha P. Väyrynen
Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, 90220, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, 90570, Finland; Department of Pathology, Oulu University Hospital, Oulu, 90220, Finland
Sara A. Väyrynen
Department of Internal Medicine, Oulu University Hospital, Oulu, 90220, Finland
Hanna Elomaa
Department of Education and Research, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland; Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland
Niko Tynkkynen
Gerontology Research Center (GEREC), Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, 40014, Finland
Tiia Eklund
Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland
Teijo Kuopio
Department of Pathology, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland; Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland
Eva-Maria Talvitie
Department of Genomics, Turku University Hospital and University of Turku, Turku, 20520, Finland
Pekka Taimen
Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku, 20520, Finland; Department of Pathology, Turku University Hospital, Turku, 20521, Finland
Markku Kallajoki
Department of Pathology, Turku University Hospital, Turku, 20521, Finland
Minna U. Kaikkonen
Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland
Merja Heinäniemi
Faculty of Health Sciences, Institute of Biomedicine, University of Eastern Finland, Kuopio, 70210, Finland
Anna-Liisa Levonen
Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland; Corresponding author. Neulaniementie 2, Bioteknia, 70211, Kuopio, Finland.
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.
