A Multi-scale, Multiomic Atlas of Human Normal and Follicular Lymphoma Lymph Nodes

Abstract

Reference atlases, molecular and spatial maps of mammalian tissues, are critical resources for discovery efforts and translational research. Their utility is dependent on operationalizing the resulting data by identifying cell types, histological patterns, and predictive biomarkers underlying health and disease. The human lymph node (LN) offers a compelling use case because of its importance in immunity, structural and cellular diversity, and neoplastic involvement. One hematological malignancy, follicular lymphoma (FL), evolves from developmentally blocked germinal center B cells residing in and trafficking through these tissues. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Here, we present an integrated portrait of healthy and FL LNs using multiple genomic and advanced imaging technologies. By leveraging the strengths of each platform, we identified several tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk of FL patients.

Advances in the multi-omics landscape of follicular lymphoma

“…Upregulation of a number of previously unidentified genes and interaction pairs such as CD70-CD27 was observed [78]. Using histology examination, the location and quantification of stromal cells was assessed in situ and showed higher abundance than common sequencing methods [12]. Together, these results indicate that the heterogeneity of microenvironment cells lies far beyond our understanding and remains to be further functionally explored.…”

“…The multi-omics approaches provide a comprehensive assessment of the biological features of disease by integrating information at different levels, including the genome, epigenome, transcriptome and proteome [11,12]. These techniques have been applied to not only comprehensively elucidate the pathogenesis and progression of the disease, but also to identify the biomarkers for improving clinical management and explore novel treatment approaches.…”

Lymph node lymphatic endothelial cells as multifaceted gatekeepers in the immune system

“…However, an important detail is that cell dissociation methods may result in significant loss of specific LN LEC types, potentially skewing the interpretation of results, as recently reported in preliminary analyses (A.J. Radtke et al, unpublished) that compared scRNA-seq data and image-based cell atlases of normal and follicular lymphoma LNs, which will require further corroboration [74]. Moreover, the effects of numerous other cancer cell types on different LEC subtypes and vice versa in affected LNs remains to be rigorously studied.…”

Mapping the lymphatic system across body scales and expertise domains: A report from the 2021 National Heart, Lung, and Blood Institute workshop at the Boston Lymphatic Symposium

“…One such technique ( Figure 4 ), Iterative Bleaching Extends multi-pleXity (IBEX) is a cyclic immunolabeling and chemical bleaching method that enables more than 50 parameters to be visualized in situ ( Radtke et al, 2020 ; Radtke et al, 2022a ) . Importantly, advanced sequencing and imaging technologies can be integrated to provide a molecular and spatial map of human tissues as recently shown for normal and follicular lymphoma LNs ( Radtke et al, 2022c ).…”

“…Remaining challenges for the field include accurate segmentation of irregularly shaped cells and deep knowledge of ill-defined cell types such as fibroblastic reticular cells. Fortunately, recent progress has been made on quantifying stromal cell types in human LNs by single cell RNA-sequencing and multiplexed imaging ( Jalkanen and Salmi, 2020 ; Abe et al, 2022 ; Radtke et al, 2022a ; Radtke et al, 2022c ).…”