A1 Journal article (refereed)
A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies (2023)
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
JYU authors or editors
Publication details
All authors or editors: Härkönen, Jouni; Pölönen, Petri; Jawahar Deen, Ashik; Selvarajan, Ilakya; Teppo, Hanna-Riikka; Dimova, Elitsa Y.; Kietzmann, Thomas; Ahtiainen, Maarit; Väyrynen, Juha P.; Väyrynen, Sara A.; et al.
Journal or series: Redox Biology
eISSN: 2213-2317
Publication year: 2023
Publication date: 27/02/2023
Volume: 61
Article number: 102644
Publisher: Elsevier
Publication country: Netherlands
Publication language: English
DOI: https://doi.org/10.1016/j.redox.2023.102644
Publication open access: Openly available
Publication channel open access: Open Access channel
Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/85978
Web address of parallel published publication (pre-print): https://www.biorxiv.org/content/10.1101/2022.05.15.489654v1
Abstract
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.
Keywords: cancer cells; transcription factors; cell signaling; immune response; T-lymphocytes; interferons
Free keywords: NRF2; KEAP1; Redox; Squamous; T cells; Interferon gamma; HLA-I; SOX2; TP63; PD-L1
Contributing organizations
Ministry reporting: Yes
Reporting Year: 2023
Preliminary JUFO rating: 2