Biology subjects

Springfeld, C.

Publications and source records attributed to Springfeld, C..

3 recordsLinked to original sources

bioRxiv2026

Hierarchical classification of immune cell transcriptomes at population-scale

Accurate immune cell classification is essential for interpreting single-cell RNA sequencing (scRNA-seq) data. However, progress in automating cell type annotation is constrained by the lack of independent, high-resolution benchmarks, as routine data integration introduces statistical dependencies that inflate model generalizability. Here, we present the single-cell universal classification omnibus (Suco), a resource of independent, uniform expert annotations, and Compocyte, a modular hierarchical classifier. Together, they establish a framework that substantially outperforms existing classifiers while facilitating expert review of ambiguous annotations. Applying Compocyte across 50 studies, including three newly generated datasets, we classified 15.6 million leukocytes from 3,965 patients. Within this cohort, we identified a new tumor-associated resorptive macrophage phenotype, a non-canonical monocyte subtype in subclinical cytokine release syndrome, and the programmatic erosion of T cell memory stemness across metastatic sites. Suco and Compocyte thus provide a generalizable framework to uncover the principles governing human immunity at population scale. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/728980v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@13a6e4borg.highwire.dtl.DTLVardef@11f1626org.highwire.dtl.DTLVardef@1e72bd4org.highwire.dtl.DTLVardef@1ee799b_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefThe single-cell universal classification omnibus and the modular hierarchical classifier Compocyte enable annotating single cell RNA sequencing data from 3,965 patients, revealing novel resorptive macrophage and vaccination-associated monocyte states, alongside the erosion of T cell memory stemness as a hallmark of solid tumor metastases. HighlightsO_LISuco, a benchmark enabling novel single cell artificial intelligence models C_LIO_LICompocyte, a hierarchical cell type classifier outperforming current architectures C_LIO_LIMacrophages adopt osteoclast-like gene expression states across cancer types C_LIO_LIStem-like programs erode in metastasis-infiltrating T memory cells across tumors C_LI

bioinformatics↗

bioRxiv2026

Cell-of-Origin, not Oncogenic Effect, Determines esmoplastic Immune Exclusion in KRAS-Driven Liver Cancer

Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the two most common primary liver cancers and share common risk factors. Yet they exhibit distinct oncogenic driver landscapes and fundamentally different tumor microenvironments (TME), with iCCA characterised by dense desmoplastic stroma that limits therapeutic efficacy. Whether these differences reflect oncogenic context or the developmental lineage of the cancer cell has remained unresolved. Here, using syngeneic orthotopic murine models derived from CRISPR-engineered cholangiocyte and hepatocyte organoids each carrying Trp53 deletion and KrasG12D mutation, we show that cell-of-origin, not oncogenic pathway activation, is the dominant determinant of TME architecture. Spatial proteomics of [~]390,000 cells reveals that cholangiocyte-derived tumors develop a stromal barrier of peripherally enriched SMA+ cancer-associated fibroblasts (CAFs) that physically excludes immune cells and elevates PD-1/PD-L1 engagement, whereas hepatocyte derived tumors permit broader immune infiltration. Transcriptional variance partitioning confirms lineage as the primary source of gene expression divergence. Integrating murine and human transcriptomic and secretomic datasets, we identify LAMC2 and uPA as cholangiocyte lineage-specific secreted factors that trigger CAF activation. Genetic deletion of either factor markedly impairs iCCA formation in vivo. These findings establish that lineage-encoded secretory programmes create a desmoplastic and immune-excluded stroma and identify LAMC2 and uPA as functionally relevant modulators of TME in KRAS-driven iCCA.

cancer biology↗

bioRxiv2021

Langerhans islets induce anti-tumor immunity at the expense of glycemic control and predict chemotherapy response in pancreatic cancer

Induction of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDA) is an unresolved challenge. Systematic investigation of the microenvironment of primary pancreatic tumors revealed a role of endocrine Langerhans islets in the coordination of immune activation. We found that intratumoral {beta}-cells, regulated via STAT3, secrete C-C motif chemokine ligand 27 (CCL27) and thereby promote a TH1 phenotype in the microenvironment resulting in an enhanced T cell infiltration and prolonged patient survival. The local effect can be abrogated in a patient-based human explant model by inhibition of the CCL27 receptor CCR10. This defense mechanism is paralleled by an impaired metabolic function of Langerhans islets with reduced insulin levels resulting in a dysregulation of glycemic control in patients. Based on these findings, screening of PDA cases (n= 2264) led to the identification of type 2 diabetes mellitus (T2DM) and extractable glycated haemoglobin (HbA1c) levels as response markers for neoadjuvant chemotherapy with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Collectively these data provide insights into the interconnection of T2DM and PDA, and link declining glycemic control to therapeutic efficacy, which can be utilized as a tool for clinical decision-making and improve patient management.

cancer biology↗