Biology subjects

Daga, N.

Publications and source records attributed to Daga, N..

3 recordsLinked to original sources

bioRxiv2025

IL-7 armed binary CAR T cell strategy to augment potency against solid tumors

Clinical studies of T cells engineered with chimeric antigen receptor (CAR) targeting CD19 in B-cell malignancies have demonstrated that relapse due to target antigen (CD19) loss or limited CAR T cell persistence is a common occurrence. The possibility of such events is greater in solid tumors, which typically display more heterogeneous antigen expression patterns and are known to directly suppress effector cell proliferation and persistence. T cell engineering strategies to overcome these barriers are being explored. However, strategies to simultaneously address both antigen heterogeneity and T cell longevity, while localizing anti-tumor effects at disease sites, remain limited. In this study we explore a dual antigen targeting strategy by directing independent CARs against the solid tumor targets PSCA and MUC1. To enhance functional persistence in a tumor-localized manner, we expressed the transgenic IL-7 cytokine and receptor (IL-7R) in respective CAR products. We now demonstrate the potency and durable antitumor effects of this binary strategy in a pancreatic tumor model.

immunology↗

bioRxiv2024

Integration of genetic and epigenetic data pinpoints autoimmune specific remodelling of enhancer landscape in CD4+ T cells

CD4+ T cells play a crucial role in adaptive immune responses and have been implicated in the pathogenesis of autoimmune diseases (ADs). Despite numerous studies, the molecular mechanisms underlying T cell dysregulation in ADs remain incompletely understood. Here, we used transcriptomic and epigenomic data from CD4+ T cells of healthy donors and patients with systemic lupus erythematosus (SLE), psoriasis, juvenile idiopathic arthritis (JIA), and Graves disease to investigate the role of enhancers in AD pathogenesis. By generating enhancer-based gene regulatory networks (eGRNs), we identified disease-specific dysregulated pathways and potential downstream target genes of enhancers harbouring AD-associated single-nucleotide polymorphisms, which we also validated using CRISPRi in primary CD4+ T cells. Our results suggest that alterations in the regulatory landscapes of CD4+ T cells, including enhancers, contribute to the development of ADs and provide a basis for developing new therapeutic approaches.

genomics↗

bioRxiv2021

GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages

Among the biggest challenges in the post-GWAS (genome-wide association studies) era is the interpretation of disease-associated genetic variants in non-coding genomic regions. Enhancers have emerged as key players in mediating the effect of genetic variants on complex traits and diseases. Their activity is regulated by a combination of transcription factors (TFs), epigenetic changes and genetic variants. Several approaches exist to link enhancers to their target genes, and others that infer TF-gene connections. However, we currently lack a framework that systematically integrates enhancers into TF-gene regulatory networks. Furthermore, we lack an unbiased way of assessing whether inferred regulatory interactions are biologically meaningful. Here we present two methods, implemented as user-friendly R packages: GRaNIE (Gene Regulatory Network Inference including Enhancers) for building enhancer-based gene regulatory networks (eGRNs) and GRaNPA (Gene Regulatory Network Performance Analysis) for evaluating GRNs. GRaNIE jointly infers TF-enhancer, enhancer-gene and TF-gene interactions by integrating open chromatin data such as ATAC-Seq or H3K27ac with RNA-seq across a set of samples (e.g. individuals), and optionally also Hi-C data. GRaNPA is a general framework for evaluating the biological relevance of TF-gene GRNs by assessing their performance for predicting cell-type specific differential expression. We demonstrate the power of our tool-suite by investigating gene regulatory mechanisms in macrophages that underlie their response to infection and cancer, their involvement in common genetic diseases including autoimmune diseases, and identify the TF PURA as putative regulator of pro-inflammatory macrophage polarisation. Availability- GRaNIE: https://bioconductor.org/packages/release/bioc/html/GRaNIE.html - GRaNPA: https://git.embl.de/grp-zaugg/GRaNPA Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

genomics↗