Suri, R. | bioRxiv Science

bioRxiv2022

A third SARS-CoV-2 mRNA vaccine dose in people receiving hemodialysis overcomes B cell defects but elicits a skewed CD4+ T cell profile

Cellular immune defects associated with suboptimal responses to SARS-CoV-2 mRNA vaccination in people receiving hemodialysis (HD) are poorly understood. We longitudinally analyzed antibody, B cell, CD4+ and CD8+ T cell vaccine responses in 27 HD patients and 26 low-risk control individuals (CI). The first two doses elicit weaker B cell and CD8+ T cell responses in HD than in CI, while CD4+ T cell responses are quantitatively similar. In HD, a third dose robustly boosts B cell responses, leads to convergent CD8+ T cell responses and enhances comparatively more Thelper (TH) immunity. Unsupervised clustering of single-cell features reveals phenotypic and functional shifts over time and between cohorts. The third dose attenuates some features of TH cells in HD (TNF/IL-2 skewing), while others (CCR6, CXCR6, PD-1 and HLA-DR overexpression) persist. Therefore, a third vaccine dose is critical to achieve robust multifaceted immunity in hemodialysis patients, although some distinct TH characteristics endure.

immunology↗

bioRxiv2022

Inflammatory Signaling and Fibroblast-Cancer Cell Interactions Transfer from a Harmonized Human Single-cell RNA Sequencing Atlas of Pancreatic Ductal Adenocarcinoma to Organoid Co-Culture

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a heterogeneous tumor microenvironment (TME) that is enriched with cancer associated fibroblasts (CAFs)1. Cell-cell interactions involving these CAFs promote an immunosuppressive phenotype with altered inflammatory gene expression. While single-cell transcriptomics provides a tool to dissect the complex intercellular pathways that regulate cancer-associated inflammation in human tumors, complementary experimental systems for mechanistic validation remain limited. This study integrated single-cell data from human tumors and novel organoid co-cultures to study the PDAC TME. We derived a comprehensive atlas of PDAC gene expression from six published human single-cell RNA sequencing (scRNA-seq) datasets2-7 to characterize intercellular signaling pathways between epithelial tumor cells and CAFs that regulate the inflammatory TME. Analysis of the epithelial cell compartment identified global gene expression pathways that modulate inflammatory signaling and are correlated with CAF composition. We then generated patient-derived organoid-CAF co-cultures to serve as a biological model of the cellular interactions learned from human tissue in the atlas. Transfer learning analysis to additional scRNA-seq data of this co-culture system and mechanistic experiments confirmed the epithelial response to fibroblast signaling. This bidirectional approach of complementary computational and in vitro applications provides a framework for future studies identifying important mechanisms of intercellular interactions in PDAC.

cancer biology↗