Integrated spatial and multimodal single‐cell transcriptomics reveal patient‐dependent cell heterogeneity in splenic marginal zone lymphoma

Biological hallmarks of splenic marginal zone lymphoma (SMZL) remain poorly described. Herein, we performed in‐depth SMZL characterization through multimodal single‐cell analyses of paired blood/spleen samples. The 3’‐single‐cell RNA‐sequencing, Cellular Indexing of Transcriptomes and Epitopes by sequencing, and 5’‐V(D)J single‐cell RNA‐sequencing datasets were integrated to characterize SMZL transcriptome profiles, including B‐cell receptor and T‐cell receptor repertoires. Hyperexpanded B‐cell clones in the spleen were at a memory‐like stage, whereas recirculating tumor B‐cells in blood encompassed multiple differentiation stages, indicating an unexpected desynchronization of the B‐cell maturation program in SMZL cells. Spatial transcriptomics showed the enrichment of T‐effector and T‐follicular helper (T FH ) signatures in the nodular subtype of SMZL. This latter also exhibited gene‐based cell–cell interactions suggestive of dynamic crosstalk between T FH and cancer cells in transcriptomics, further substantiated by using imaging mass cytometry. Our findings provide a comprehensive high‐resolution description of SMZL biological hallmarks and characterize, for the first time in situ , inter‐ and intra‐patient heterogeneity at both transcriptomic and protein levels.