Biology subjects

Schulze-Osthoff, K.

Publications and source records attributed to Schulze-Osthoff, K..

5 recordsLinked to original sources

bioRxiv2026

Alternative lengthening of telomeres stratifies complex karyotype sarcomas into distinct genomic and transcriptomic states

Complex karyotype sarcomas (CKS) are heterogeneous mesenchymal malignancies that typically lack recurrent actionable oncogenic drivers and remain therapeutically challenging. Loss of ATRX is a recurrent feature of CKS and defines a particularly high-risk subgroup. ATRX loss is also associated with activation of the alternative lengthening of telomeres (ALT) pathway, and ALT-positive sarcomas have been linked to poor clinical outcomes. However, the molecular underpinnings underlying ALT-status-dependent differences in CKS, as well as the therapeutic vulnerabilities associated with ALT, remain poorly defined. By integrating C-circle-based ALT detection across 776 sarcoma samples with multi-modal sequencing of five CKS subtypes, we find that ALT activity is associated with enriched hallmarks of genomic instability. ALT-positive transcriptomes are dominated by a coordinated DNA damage response and mitotic program, in contrast to oncogenic signaling pathways that drive TERT activation in ALT-negative tumors. Long-read sequencing reveals telomere repeat clusters and telomere-mediated healing at structural breakpoints in ALT-positive tumors. These events also occur on extrachromosomal DNA (ecDNA), linking ALT activity to ecDNA biology. Together, our findings position ALT status as an important stratifying feature of CKS and identify ALT-associated transcriptional programs as potential therapeutic targets.

cancer biology↗

bioRxiv2026

Treg-derived IκBζ promotes their conversion into Th2-like effectors and drives type 2 inflammation via BATF

Regulatory T cells (Treg cells) maintain peripheral immune tolerance but display considerable plasticity in peripheral tissues. The molecular mechanisms governing their function and plasticity, particularly under inflammatory conditions, remain poorly defined. Here, we identify the NF-{kappa}B-associated transcriptional cofactor I{kappa}B{zeta} as a critical regulator of Treg cell plasticity and function. Enforced expression of I{kappa}B{zeta} in Treg cells triggered the excessive expansion of functionally impaired Treg cells, resulting in lymphadenopathy, splenomegaly, and systemic type 2 inflammation, most prominently in the lung. Mechanistically, I{kappa}B{zeta} modified BATF expression and function, thereby driving the cell-intrinsic production of Th2-associated cytokines by Treg cells. Conversely, Treg-specific deletion of I{kappa}B{zeta} constrained IL-33-mediated expansion of tissue Treg cells and surprisingly attenuated type 2 inflammation. Thus, I{kappa}B{zeta} functions as a molecular switch that reprograms regulatory T cells into Th2-like Treg cells, thereby perturbing peripheral immune tolerance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/707402v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ef0b17org.highwire.dtl.DTLVardef@c12eaaorg.highwire.dtl.DTLVardef@decc86org.highwire.dtl.DTLVardef@1458767_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Constitutive expression of IκBζ promotes tumor growth and immunotherapy resistance in melanoma

BackgroundI{kappa}B{zeta}, a rather unknown co-regulator of NF-{kappa}B, is mostly inducibly expressed and can either activate or repress a specific subset of NF-{kappa}B target genes. While its role as a transcriptional regulator of various cytokines and chemokines in immune cells has been revealed, I{kappa}B{zeta}s function in solid cancer remains unclear. MethodsWe investigated I{kappa}B{zeta} expression in melanoma, and assessed its impact on target gene expression, tumor growth, and response to immunotherapy in melanoma cell lines, mouse models, and patient samples. ResultsUnlike in other cell types, I{kappa}B{zeta} protein was found to be constitutively expressed in a subfraction of melanoma cell lines, and around 35% of melanoma cases. This atypical expression pattern of I{kappa}B{zeta} did not correlate with its mRNA levels or known driver mutations, but instead seemed to result from changes in its post-transcriptional or post-translational regulation. Deleting constitutively expressed I{kappa}B{zeta} abrogated the activity and chromatin association of STAT3 and p65, leading to reduced expression of the pro-proliferative cytokines IL-1{beta} and IL-6 in melanoma cells. Consequently, loss of tumor-derived I{kappa}B{zeta} suppressed self-sustained melanoma cell growth both in vitro and in vivo. Additionally, constitutive I{kappa}B{zeta} expression suppressed the induction of the chemokines CXCL9, CXCL10, and CCL5, which impaired the recruitment of NK and CD8+ T-cells to the tumor, causing resistance to -PD-1 immunotherapy in mice. Furthermore, the expression of tumor-derived I{kappa}B{zeta} also correlated with the absence of CD8+ T-cells in human melanoma samples and progressive disease during immunotherapy. ConclusionWe propose that tumor-derived I{kappa}B{zeta} could serve as a new therapeutic target and prognostic marker that characterizes melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses. Targeting I{kappa}B{zeta} expression might open up a new therapy option to re-establish the recruitment of cytotoxic cells, thereby resensitizing for immunotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/613946v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@76389aorg.highwire.dtl.DTLVardef@17e3f1eorg.highwire.dtl.DTLVardef@161d491org.highwire.dtl.DTLVardef@1ca9f2d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date.\n\nWe analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (N = 496) and a validation set (DKTK MASTER cohort, N = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately re-analyzed.\n\nAmong HPV-negative HNSCC, APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. APOBEC3-enriched HPV-negative HNSCC showed higher T-cell inflammation and immune checkpoint expression. Mutations in immune-evasion pathways were enriched in these tumors. APOBEC3B and 3C expression was identified in tumor cells and correlated with tumor inflammation.\n\nWe identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.

cancer biology↗

bioRxiv2018

Is IκBζ constitutively expressed in mammalian airway epithelium?

I{kappa}B{zeta} is a transcriptional factor induced primarily in immune cells upon Toll-like receptor (TLR) activation that drives important cytokine responses. Recent studies have demonstrated constitutive I{kappa}B{zeta} expression in the epithelial cells of mouse skin and eyes, possibly reflecting the activation of TLRs by pathogen-associated molecular patterns (PAMPs). In this context, another mucosal surface, the lung epithelium, may not be as actively exposed to the external environment as the skin and the conjunctiva, especially since the lower lung airways are typically conceived to be sterile. Whether I{kappa}B{zeta} expression in the lungs is constitutive or induced remains largely unexplored. This is especially important since I{kappa}B{zeta} has been shown to promote the expression of protective cytokine and antimicrobial peptide responses, supporting a role for I{kappa}B{zeta} in lung host defense. We hence evaluated I{kappa}B{zeta} expression in airway epithelia of both humans and mice using immunostaining with antiserum raised against recombinant I{kappa}B{zeta} in our laboratory. We observed positive signal in the nuclei of ciliated epithelial cells lining the central airways. Airway cells of gnotobiotic mice also stained positive, suggesting that I{kappa}B{zeta} expression does not require induction by bacterial PAMPs. Unexpectedly, we also observed staining in the lung epithelia of I{kappa}B{zeta} knockout mice, indicating possible false positive signals from our immunohistochemistry experiments. In this context, 2D gel analysis followed by mass spectrometry revealed that our I{kappa}B{zeta} antiserum also detected a nuclear protein lamin B1. Nevertheless, immunoblotting tissue homogenates from gnotobiotic mouse lungs and primary human airway epithelial cells showed the appropriate 86 kDa band for I{kappa}B{zeta}. Together, these results demonstrate constitutive I{kappa}B{zeta} expression in airway epithelium, suggesting that lung epithelial cells may depend upon I{kappa}B{zeta} expression for airway protection.

immunology↗