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 editorsHärkönen, 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 seriesRedox Biology

eISSN2213-2317

Publication year2023

Publication date27/02/2023

Volume61

Article number102644

PublisherElsevier

Publication countryNetherlands

Publication languageEnglish

DOIhttps://doi.org/10.1016/j.redox.2023.102644

Publication open accessOpenly available

Publication channel open accessOpen 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.


Keywordscancer cellstranscription factorscell signalingimmune responseT-lymphocytesinterferons

Free keywordsNRF2; KEAP1; Redox; Squamous; T cells; Interferon gamma; HLA-I; SOX2; TP63; PD-L1


Contributing organizations


Ministry reportingYes

Reporting Year2023

Preliminary JUFO rating2


Last updated on 2024-25-03 at 09:57