Biology subjects

Imbusch, C.

Publications and source records attributed to Imbusch, C..

4 recordsLinked to original sources

bioRxiv2024

Quantifying immune cell telomere content at single-cell resolution in context of PD-1 checkpoint immunotherapy

Biological processes such as aging, carcinogenesis, and immune responses depend on the ability of cells to maintain or rapidly expand populations. This capacity is constrained by a cells replicative potential, which is reflected in its telomere content. Despite the central role of telomeres in cancer and immunity, their analysis at single-cell resolution across diverse cell types remains challenging. Here we show that scATAC-seq data enables quantitative telomeromics when key technical and biological confounders are accounted for. We present a computational framework that addresses read sparsity, telomere representation, and chromatin-state-dependent competition for sequencing signal, enabling robust estimation of telomere content and telomeric variant repeat composition from scATAC-seq data. By inferring global chromatin condensation directly from scATAC-seq profiles, our approach corrects for cell-cycle-associated biases while simultaneously capturing chromatin-state dysregulation in cancer. Applied to a large cancer atlas, this framework reveals patient-specific telomere maintenance phenotypes, including telomerase-associated and alternative lengthening of telomeres (ALT)-like profiles preserved across subclonal populations. Extending beyond cancer cells, we observe that telomere content in exhausted T cell subpopulations prior to immunotherapy is predictive for effective response to PD-1 checkpoint blockade. Together, these results establish scATAC-seq as a robust platform for single-cell telomeromics in cancer and immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/609339v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@4f9498org.highwire.dtl.DTLVardef@a4b787org.highwire.dtl.DTLVardef@d1e25org.highwire.dtl.DTLVardef@136196b_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Popp, F. (2026) https://BioRender.com/mi2jove

immunology↗

bioRxiv2023

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

The long-term consequences of cancer or cancer therapy on the patients immune system years after cancer-free survival remain poorly understood. Here, we have performed an in-depth characterization of the bone marrow ecosystem of multiple myeloma long-term survivors at initial diagnosis and up to 17 years following cancer-free survival. Using comparative single-cell analyses in combination with molecular, genomic and functional approaches, we demonstrate that multiple myeloma long-term survivors display pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently driven by an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible immunological scarring caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of multiple myeloma long-term survivors, revealing reversible and irreversible alterations of the immune compartment, which can serve as diagnostic and predictive tools. Statement of significanceLarge-scale single-cell profiling of a unique cohort of multiple myeloma long-term survivors uncovered that exposure to cancer and its treatment causes both reversible and irreversible immune alterations associated with impaired immunity. These findings have far-reaching implications for the understanding of long-term immune alterations in cancer, which need to be considered also in the context of immune therapeutic approaches. Furthermore, our study demonstrates how cancer-associated immune trafficking can be used to predict disease re-initiation in the bone marrow, opening new avenues for minimally invasive disease monitoring.

cancer biology↗

bioRxiv2022

Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer

Chromosomal instability (CIN), the inability to correctly segregate chromosomes during cell division, is a common characteristic of solid tumors. CIN contributes to tumor evolution by promoting intratumor heterogeneity, thus facilitating resistance to cancer therapies. In vitro studies have demonstrated that cells with complex karyotypes are recognized and eliminated by natural killer (NK) cells. Paradoxically, it has also been observed that human tumors with high levels of CIN have an immunosuppressive phenotype. It remains unclear which CIN-associated molecular features alter immune recognition during tumor evolution. Previous studies with Polo-like kinase 1 (Plk1) overexpression in Her2-positive breast tumors, resulted in increased levels of CIN and delayed tumorigenesis. Using this mouse model, we show that high CIN tumors activate a senescence-associated secretory phenotype (SASP) and become immune evasive by activating RELB signaling and upregulating PD-L1 in a non-cell-autonomous manner. Single-cell RNA sequencing of immune cells from early-stage induced mammary glands revealed that macrophages, NK cells, B cells and regulatory T cells are programmed to a suppressive phenotype during tumor development. In human tumors, we further establish the importance of RELB/p38 signaling in understanding the interplay between CIN and the immune system, highlighting the need for novel adjuvant therapies in the context of chromosomally unstable tumors.

cancer biology↗

bioRxiv2022

High-resolution epigenetic profiling identifies novel regulators of COPD in human lung fibroblasts

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering the environmental cause of COPD (e.g., cigarette smoke) and disease phenotypes, including stem-cell senescence and impaired differentiation, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) isolated from distal parenchyma of ex-smoker controls and COPD patients, with both mild and severe disease. The epigenetic landscape is markedly changed in lung fibroblasts across COPD stages, with DNA methylation changes occurring predominantly in regulatory regions, including promoters and enhancers. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Notably, we identified epigenetic and transcriptional dysregulation already in mild COPD patients, providing unique insights into early disease. Integration of profiling data identified 110 candidate regulators of disease phenotypes, including epigenetic factors. Using phenotypic screens, we verified the regulator capacity of multiple candidates and linked them to repair processes in the human lung. Our study provides first integrative high-resolution epigenetic and transcriptomic maps of human lung fibroblasts across stages of COPD. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic respiratory diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients.

cell biology↗