The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma.

Biological heterogeneity in diffuse large B cell lymphoma (DLBCL) is partly driven by cell-of-origin subtypes and associated genomic lesions, but also by diverse cell types and cell states in the tumor microenvironment (TME). However, dissecting these cell states and their clinical relevance at scale remains challenging. Here, we implemented EcoTyper, a machine-learning framework integrating transcriptome deconvolution and single-cell RNA sequencing, to characterize clinically relevant DLBCL cell states and ecosystems. Using this approach, we identified five cell states of malignant B cells that vary in prognostic associations and differentiation status. We also identified striking variation in cell states for 12 other lineages comprising the TME and forming cell state interactions in stereotyped ecosystems. While cell-of-origin subtypes have distinct TME composition, DLBCL ecosystems capture clinical heterogeneity within existing subtypes and extend beyond cell-of-origin and genotypic classes. These results resolve the DLBCL microenvironment at systems-level resolution and identify opportunities for therapeutic targeting (https://ecotyper.stanford.edu/lymphoma). [Display omitted] • Large-scale profiling of cell states & cellular ecosystems in hematologic malignancies • Atlas of malignant B cell states and 12 cell types in the DLBCL tumor microenvironment • Nine DLBCL cellular ecosystems & their relationships to molecular subtypes and survival • Candidate cellular biomarkers of response to bortezomib in DLBCL Steen et al. implement EcoTyper, a machine-learning approach for dissecting cellular heterogeneity in the most common blood cancer, diffuse large B cell lymphoma (DLBCL). Forty-four cell states spanning malignant cells and the microenvironment are defined, uncovering a rich landscape of cellular ecosystems that extend beyond traditional DLBCL classifications, revealing new opportunities for therapy selection. [ABSTRACT FROM AUTHOR]