Biology subjects

Kuebler, A.

Publications and source records attributed to Kuebler, A..

3 recordsLinked to original sources

bioRxiv2026

Mapping the immune landscape in small cell lung cancer unveils a distinct tumor-reactive CD8+ T cell molecular signature

Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic advances. Unlike many other cancers, its immune landscape, particularly immune competence and T cell recognition, remains poorly characterized. Here, we generate a single-cell transcriptome atlas of the SCLC immune microenvironment with paired T cell receptor (TCR) sequencing. By linking T cell states with clonality and a multilayered functional screening, we identify 6 tumor-reactive TCRs that recognize and eradicate autologous SCLC cell lines. We delineate a novel SCLC-reactive CD8+ T cell signature (SCLC_TR), enabling the identification of 47 further SCLC-reactive TCRs. The SCLC_TR signature performs extremely well in pancreatic ductal adenocarcinoma (PDAC), another immune-cold tumor indication, and, most strikingly, patients with elevated SCLC_TR signature scores exhibited significantly improved survival, underlining its prognostic potential. Comparative cell-cell interaction analyses implicate several immunosuppressive mechanisms, with myeloid cells and CD4 regulatory T cells possibly acting as counterbalances to effector T cell activity in SCLC. In summary, our study challenges the prevailing notion of SCLC as an immune-cold tumor type by providing direct evidence of tumor-reactive T cell responses and introduces the SCLC_TR signature as a tool to identify tumor-specific T cells and their microenvironmental restraints and escape mechanisms, ultimately shaping next-generation immunotherapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/735200v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1c25f2eorg.highwire.dtl.DTLVardef@1f6f519org.highwire.dtl.DTLVardef@553e57org.highwire.dtl.DTLVardef@6fe7e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Epigenetic control of S100A8/A9-driven monocytic inflammation licenses anti-leukemic functionality of immature NK cells during hematopoietic stem cell differentiation.

Inflammation is a key driver of hematopoietic dysfunction in myeloid malignancies, but its role in the context of hypomethylating therapy remains incompletely understood. Although 5-Azacytidine is used posttransplant in high-risk myelodysplastic syndrome (MDS), only 50% of patients show a clinical response. We provide evidence that inherent inflammatory properties of healthy donor CD34+ stem cells exist that are likely to contribute to the "response" seen in MDS patients. These are linked to epigenetic priming of the myeloid niche, resulting in S100A8/A9-driven inflammatory program that promotes functionality of immature NK cells. Using in vitro differentiation systems, multi-omic profiling, and a S100A9-/- mouse model, we find that 5-AzaC modulates inflammatory transcriptional programs through epigenetic rewiring of upstream regulatory elements. Loss of S100A9 disrupts myeloid differentiation, impairs NK cell maturation, and alters key developmental regulators including CEBPB, JUN, and NFIL3. In vivo, 5-AzaC restores these defects and primes NK cells in a time- and context-dependent manner. Re-analysis of the published Australian MDS/CMML cohort shows that "responders" display increased S100A8/A9 expression together with enhanced IFN-{gamma}, IL6-JAK-STAT3, and TNF signaling. These findings suggest that inflammatory myeloid programs may serve as predictive biomarkers and therapeutic targets to enhance NK cell-mediated graft-versus-leukemia activity posttransplant. SummaryO_LIWe provide compelling evidence that inherent properties of healthy donor CD34+ hematopoietic stem cells (SCs) exist that are likely to contribute to the "response" seen upon pre-emptive posttransplant 5-AzaC therapy of patients with high-risk myelodysplastic syndrome (MDS). C_LIO_LIThese properties are linked to a distinct form of epigenetic plasticity at upstream-located transcription factor (TF) binding sites. This may indirectly contribute to acute S100A8/A9-driven inflammation, which is demonstrable in distinct monocyte subsets and, importantly, also in NK cells thereby determining the characteristics of inflammatory monocyte-NK cell crosstalk. C_LIO_LIMice with a targeted deletion of S100A9 fail to upregulate CEBPB / JUN and NFIL3 which results in impaired myeloid priming and dysfunctional NK cell maturation, respectively. C_LIO_LIRe-analysis of the Australian MDS/CMML cohort confirms that MDS patients that "respond" to 5-AzaC exhibit activated IFN-{gamma}, IL6-JAK-STAT3, and TNF-signaling pathways in the context of upregulated S100A8/A9 after six months of treatment. C_LIO_LIOur study indicates that screening of healthy donors SCs for specific inflammatory markers in early developing monocytes could be used as a marker to predict which donor will have the potential of generating a S100A8/A9-driven inflammatory response. This may help identify patients with MDS as well as AML who are likely to benefit from low-dose, short-term 5-AzaC therapy as early as day 7 after transplantation, potentially resulting in increased graft-versus-leukemia (GvL) activity. C_LI

immunology↗

bioRxiv2023

Modulation of Human Frontal Midline Theta by Neurofeedback: A Systematic Review and Quantitative Meta-Analysis

Human brain activity consists of different frequency bands associated with varying functions. Oscillatory activity of frontal brain regions in the theta range (4-8Hz) is linked to cognitive processing and can be modulated by neurofeedback - a technique where participants receive real-time feedback about their brain activity and learn to modulate it. However, criticism of this technique evolved, and high heterogeneity of study designs complicates a valid evaluation of its effectiveness. This meta-analysis provides the first systematic overview over studies attempting to modulate frontal midline theta with neurofeedback in healthy human participants. Out of 1431 articles screened, 14 studies were eligible for systematic review and 11 for quantitative meta-analyses. Studies were evaluated following the DIAD model and the PRISMA guidelines. A significant across-study effect of medium size (Hedges g = .66; 95%-CI [-0.62, 1.73]) with substantial between-study heterogeneity (Q(16) = 167.43, p < .0001) was observed and subanalysis revealed effective frontal midline theta upregulation. We discuss moderators of effect sizes and provide guidelines for future research in this dynamic field.

neuroscience↗