A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies
Härkönen, J., Pölönen, P., Jawahar Deen, A., Selvarajan, I., Teppo, H.-R., Dimova, E. Y., Kietzmann, T., Ahtiainen, M., Väyrynen, J. P., Väyrynen, S. A., Elomaa, H., Tynkkynen, N., Eklund, T., Kuopio, T., Talvitie, E.-M., Taimen, P., Kallajoki, M., Kaikkonen, M., Heinäniemi, M., & Levonen, A.-L. (2023). A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies. Redox Biology, 61, Article 102644. https://doi.org/10.1016/j.redox.2023.102644
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Redox BiologyAuthors
Date
2023Discipline
Solu- ja molekyylibiologiaGerontologian tutkimuskeskusHyvinvoinnin tutkimuksen yhteisöCell and Molecular BiologyGerontology Research CenterSchool of WellbeingCopyright
© 2023 The Authors. Published by Elsevier B.V.
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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ElsevierISSN Search the Publication Forum
2213-2317Keywords
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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. ...License
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