Spatial Analysis of the Tumor Microenvironment in Diffuse Large B-Cell Lymphoma Reveals Clinically Relevant Cell Interactions and Recurrent Cellular Neighborhoods

Recent studies have explored the composition of tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL) However, cell-to-cell interactions, along with the spatial organization of DLBCL TME and their impact on patient outcomes, have remained poorly characterized. We ap-plied multiplexed immunofluorescence, cell phenotyping, and neighborhood analysis to investigate 1,218,756 single cells in 99 samples from patients with primary DLBCL. We identified 17 cell pheno-types and 10 recurrent cellular neighborhoods (RCNs) across samples, subdividing DLBCLs into immune-poor areas and areas with diverse immune cell infiltrates. Avoidance of B cells and PD-1+ T cells was associated with less aggressive clinical characteristics and favorable survival. Like-wise, the proximity of CD8+ T cell-rich and immune-poor RCNs translated to favorable, and the proximity of PD-L1+ B cell-rich and CD8+ T cell-rich RCNs to unfavorable patient outcomes. Our findings provide insights into the spatial interactions and organization of DLBCL TME with implica-tions for patient outcomes.