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Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large
Min Liu1,2,3, Giorgio Bertolazzi4,5, Shruti Sridhar1
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Insights
This study maps macrophages in lymphoma, revealing distinct subtypes and spatial patterns. These macrophage signatures offer new insights into diffuse large B-cell lymphoma (DLBCL) subtypes and patient survival.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Macrophages are key immune cells in the diffuse large B-cell lymphoma (DLBCL) microenvironment.
- Current methods like immunohistochemistry lack comprehensive subtype analysis and show variable prognostic value in DLBCL.
Purpose of the Study:
- To spatially characterize macrophages in reactive lymphoid tissues (RLTs) and DLBCL using whole transcriptome analysis.
- To identify distinct macrophage subtypes and their spatial distribution within different tissue niches.
- To develop and validate macrophage signatures (MacroSigs) associated with DLBCL biology and clinical outcomes.
Main Methods:
- Digital spatial profiling and whole transcriptome analysis of CD68+ cells.
- Transcriptomic analysis of macrophages in distinct spatial niches of RLTs and DLBCL.
- Generation of six spatially-derived macrophage signatures (MacroSigs).
- Interrogation of MacroSigs in single-cell RNA-sequencing and DLBCL cohort gene-expression data.
Main Results:
- Transcriptomic differences were identified between macrophages in RLTs and DLBCL, and within specific RLT niches.
- Six spatially-derived macrophage signatures (MacroSigs) were generated.
- Specific MacroSigs correlated with DLBCL cell-of-origin subtypes and overall survival.
Conclusions:
- This study presents a spatially-resolved atlas of macrophages in reactive and malignant lymphoid tissues.
- The identified macrophage signatures highlight their biological and clinical significance in DLBCL.
- This work provides a foundation for understanding macrophage heterogeneity in lymphoma.
Abstract:
Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.
