Biology subjects

Porter, C. B. M.

Publications and source records attributed to Porter, C. B. M..

5 recordsLinked to original sources

bioRxiv2026

Type 1 immunity linked to CMV exposure improves long-term survival in sepsis without shock

Dysregulated immune responses are at the core of sepsis pathology and can drive both acute organ dysfunction and long-term morbidity and mortality. To better understand the association between specific immune histories, perturbations and sepsis outcomes, we combined immune phenotyping, functional cytokine production assays and antibody repertoire profiling. While sepsis immune profiles were highly heterogeneous, we identified a strong association between the frequency of CXCR3-expressing CD4 memory T cells at time of enrollment and six-month survival in sepsis without shock. Surprisingly, the same population was linked to improved organ function trajectories in septic shock patients but did not influence six-month survival, highlighting the importance of considering physiological states to define immune predictors. Finally, phage display profiling revealed that these Th1 cells were generally expanded in CMV-seropositive individuals, suggesting that previous and latent infections may modulate sepsis outcomes.

immunology↗

bioRxiv2024

A spatial cell atlas of neuroblastoma reveals developmental, epigenetic and spatial axis of tumor heterogeneity

Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage with complex inter- and intra-tumoral heterogeneity. To chart this complexity, we generated a comprehensive cell atlas of 55 neuroblastoma patient tumors, collected from two pediatric cancer institutions, spanning a range of clinical, genetic, and histologic features. Our atlas combines single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, whole exome sequencing, DNA methylation profiling, spatial transcriptomics, and two spatial proteomic methods. Sc/snRNA-seq revealed three malignant cell states with features of sympathoadrenal lineage development. All of the neuroblastomas had malignant cells that resembled sympathoblasts and the more differentiated adrenergic cells. A subset of tumors had malignant cells in a mesenchymal cell state with molecular features of Schwann cell precursors. DNA methylation profiles defined four groupings of patients, which differ in the degree of malignant cell heterogeneity and clinical outcomes. Using spatial proteomics, we found that neuroblastomas are spatially compartmentalized, with malignant tumor cells sequestered away from immune cells. Finally, we identify spatially restricted signaling patterns in immune cells from spatial transcriptomics. To facilitate the visualization and analysis of our atlas as a resource for further research in neuroblastoma, single cell, and spatial-omics, all data are shared through the Human Tumor Atlas Network Data Commons at www.humantumoratlas.org.

cancer biology↗

bioRxiv2021

Parental-fetal interplay of immune genes leads to intrauterine growth restriction

Intrauterine growth restriction (IUGR) of fetuses affects 5-10% of pregnancies and is associated with perinatal morbidity, mortality and long-term health issues. Understanding genetic predisposition to IUGR is challenging, owing to extensive gene polymorphisms, linkage disequilibrium, and maternal and paternal influence. Here, we demonstrate that the inhibitory receptor, KIR2DL1, expressed on maternal uterine natural killer (uNK) cells, in interaction with the paternally-inherited HLA-C*05, an HLA-C group 2 allotype, expressed on fetal trophoblast cells, causes IUGR in a humanised mouse model. Micro-CT imaging of the uteroplacental vasculature revealed reduced uterine spiral artery diameter and increased segment length, increasing fetal blood flow resistance. Single cell RNA-Seq from the maternal-fetal interface highlighted expression programs activated by KIR2DL1-induced IUGR in several placental cell types, including degradation of extracellular matrix components, angiogenesis, and uNK cell communication, suggesting a complex response underlying IUGR. As current IUGR treatments are insufficient, our findings provide important insight for drug development.

immunology↗

bioRxiv2019

A single-cell and single-nucleus RNA-seq toolbox for fresh and frozen human tumors

Single cell genomics is essential to chart the complex tumor ecosystem. While single cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumor tissues, single nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each strategy requires modifications to fit the unique characteristics of different tissue and tumor types, posing a barrier to adoption. Here, we developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We tested eight tumor types of varying tissue and sample characteristics (resection, biopsy, ascites, and orthotopic patient-derived xenograft): lung cancer, metastatic breast cancer, ovarian cancer, melanoma, neuroblastoma, pediatric sarcoma, glioblastoma, pediatric high-grade glioma, and chronic lymphocytic leukemia. Analyzing 212,498 cells and nuclei from 39 clinical samples, we evaluated protocols by cell quality, recovery rate, and cellular composition. We optimized protocols for fresh tissue dissociation for different tumor types using a decision tree to account for the technical and biological variation between clinical samples. We established methods for nucleus isolation from OCT embedded and fresh-frozen tissues, with an optimization matrix varying mechanical force, buffer, and detergent. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types and intrinsic expression profiles, but at different proportions. Our work provides direct guidance across a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.

genomics↗

bioRxiv2018

Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors

Psoriasis pathology is driven by the type 3 cytokines IL-17 and Il-22, but little is understood about the dynamics that initiate alterations in tissue homeostasis. Here, we use mouse models, single-cell RNA-seq (scRNA-seq), computational inference and cell lineage mapping to show that psoriasis induction reconfigures the functionality of skin-resident ILCs to initiate disease. Tissue-resident ILCs amplified an initial IL-23 trigger and were sufficient, without circulatory ILCs, to drive pathology, indicating that ILC tissue remodeling initiates psoriasis. Skin ILCs expressed type 2 cytokines IL-5 and IL-13 in steady state, but were epigenetically poised to become ILC3-like cells. ScRNA-seq profiles of ILCs from psoriatic and naive skin of wild type (WT) and Rag1-/- mice form a dense continuum, consistent with this model of fluid ILC states. We inferred biological \"topics\" underlying these states and their relative importance in each cell with a generative model of latent Dirichlet allocation, showing that ILCs from untreated skin span a spectrum of states, including a naive/quiescent-like state and one expressing the Cd74 and Il13 but little Il5. Upon disease induction, this spectrum shifts, giving rise to a greater proportion of classical Il5- and Il13- expressing \"ILC2s\" and a new, mixed ILC2/ILC3-like subset, expressing Il13, Il17, and Il22. Using these key topics, we related the cells through transitions, revealing a quiescence-ILC2-ILC3s state trajectory. We demonstrated this plasticity in vivo, combining an IL-5 fate mouse with IL-17A and IL-22 reporters, validating the transition of IL-5-producing ILC2s to IL-22- and IL-17A-producing cells during disease initiation. Thus, steady-state skin ILCs are actively repressed and cued for a plastic, type 2 response, which, upon induction, morphs into a type 3 response that drives psoriasis. This suggests a general model where specific immune activities are primed in healthy tissue, dynamically adapt to provocations, and left unchecked, drive pathological remodeling.

immunology↗