Kolb Antonia, Kulis-Mandic Ana-Marija, Klein Matthias, Stastny Anna, Haist Maximilian, Votteler Vanessa, Weidenthaler-Barth Beate, Sinnberg Tobias, Sucker Antje, Allies Gabriele, Albrecht Lea Jessica, Tasdogan Alpaslan, Tuettenberg Andrea, Gaida Matthias M, Deppermann Carsten, Stege Henner, Schadendorf Dirk, Grabbe Stephan, Schulze-Osthoff Klaus, Kramer Daniela
Department of Dermatology, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
Institute for Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Nat Commun. 2025 Jun 25;16(1):5387. doi: 10.1038/s41467-025-60929-5.
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.
IκBζ是一种相对不太知名的NF-κB协同调节因子，它可以激活或抑制一部分NF-κB靶基因。虽然其作为免疫细胞中细胞因子和趋化因子的诱导性表达转录调节因子的作用已得到确立，但IκBζ在实体癌中的功能仍不清楚。在此我们表明，IκBζ蛋白在一部分黑色素瘤细胞系中组成性表达，在所有黑色素瘤病例中约占30%，与它的mRNA水平或已知突变无关。在黑色素瘤中删除IκBζ可消除STAT3和NF-κB的活性及与染色质的结合，从而降低促增殖细胞因子IL-1β和IL-6的表达，进而损害黑色素瘤细胞的生长。此外，IκBζ通过HDAC3和EZH2抑制Cxcl9、Cxcl10和Ccl5的表达，这会损害NK细胞和CD8 T细胞向肿瘤的募集，导致小鼠对α-PD-1免疫疗法产生抗性。因此，肿瘤来源的IκBζ可能作为具有高肿瘤细胞增殖、细胞毒性T细胞和NK细胞排除以及不良免疫治疗反应的黑色素瘤的治疗靶点和预后标志物。
