A Spatially Resolved Dark- Versus Light-Zone Microenvironment Signature Subdivides Germinal Center-Related Aggressive B-Cell Lymphomas

We applied digital spatial profiling for 87 immune and stromal genes to lymph node germinal center (GC) dark- and light-zone (DZ/LZ) regions of interest to obtain a differential gene signature of these two distinct microenvironments. The spatially-resolved 53-genes signature, comprising key genes of the DZ mutational machinery, and LZ immune milieu, was applied to the transcriptomes of 543 GC-related Diffuse Large B-cell Lymphomas and double-hit (DH) lymphomas. According to the DZ/LZ signature, the GC-related lymphomas were sub-classified into two clusters. The two subgroups differed in the distribution of DH cases and survival, with most DH displaying a distinct DZ-like profile. The clustering analysis was also performed using a 25-genes signature composed of DZ/LZ genes represented in the non-B, stromal sub-compartments, for the first time achieving a DZ/LZ discrimination based on stromal microenvironment features. The report offers new insight into the GC' microenvironment, hinting to a DZ origin of DH lymphomas.