Journal Article

DKFZ-2025-01290

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance.

Kolb, A. ; Kulis-Mandic, A.-M. ; Klein, M. ; Stastny, A. ; Haist, M. ; Votteler, V.DKFZ* ; Weidenthaler-Barth, B. ; Sinnberg, T. ; Sucker, A.DKFZ* ; Allies, G.DKFZ* ; Albrecht, L. J.DKFZ* ; Tasdogan, A.DKFZ* ; Tuettenberg, A. ; Gaida, M. M. ; Deppermann, C. ; Stege, H. ; Schadendorf, D.DKFZ* ; Grabbe, S. ; Schulze Osthoff, K.DKFZ* ; Kramer, D.

2025
Springer Nature [London]

This record in other databases:  

Please use a persistent id in citations: doi:10.1038/s41467-025-60929-5

Abstract: IκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ's function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppresses Cxcl9, Cxcl10, and Ccl5 expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8+ T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.

Keyword(s): Melanoma: genetics (MeSH) ; Melanoma: pathology (MeSH) ; Melanoma: therapy (MeSH) ; Melanoma: immunology (MeSH) ; Melanoma: metabolism (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Cell Line, Tumor (MeSH) ; STAT3 Transcription Factor: metabolism (MeSH) ; Cell Proliferation (MeSH) ; Immunotherapy (MeSH) ; NF-kappa B: metabolism (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Enhancer of Zeste Homolog 2 Protein: metabolism (MeSH) ; Enhancer of Zeste Homolog 2 Protein: genetics (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Killer Cells, Natural: immunology (MeSH) ; Chemokine CXCL10: genetics (MeSH) ; Chemokine CXCL10: metabolism (MeSH) ; Chemokine CCL5: metabolism (MeSH) ; Chemokine CCL5: genetics (MeSH) ; I-kappa B Proteins: genetics (MeSH) ; I-kappa B Proteins: metabolism (MeSH) ; Chemokine CXCL9: metabolism (MeSH) ; Chemokine CXCL9: genetics (MeSH) ; Interleukin-6: metabolism (MeSH) ; Interleukin-6: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Female (MeSH) ; Histone Deacetylases (MeSH) ; Adaptor Proteins, Signal Transducing (MeSH) ; STAT3 Transcription Factor ; NF-kappa B ; Enhancer of Zeste Homolog 2 Protein ; histone deacetylase 3 ; STAT3 protein, human ; Chemokine CXCL10 ; Chemokine CCL5 ; NFKBIZ protein, human ; I-kappa B Proteins ; EZH2 protein, human ; Chemokine CXCL9 ; Interleukin-6 ; Histone Deacetylases ; Adaptor Proteins, Signal Transducing

---

Contributing Institute(s):

1. DKTK Koordinierungsstelle Tübingen (TU01)
2. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

---

Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---