Spatial Proteomics Reveals Dual-Compartment Immune Evasion Architecture and Core Lymphomagenic Stromal Niches in Follicular Lymphoma

Follicular lymphomas (FL) depend on microenvironmental signals for survival, and the composition of the tumor microenvironment may influence clinical outcome. How it is spatially organized, and how that organization drives immune evasion, has not been established. We applied two complementary 39-marker imaging mass cytometry panels to 156 follicular lymphoma tumor cores, generating a spatial atlas of 4.2 million cells resolved into nine tissue compartments. FL follicles operated as immune-privileged zones: CD8 T cells were largely excluded, and those that did infiltrate were exhausted in a gradient that peaked at the GC core and dissolved at the follicle boundary. A Treg-enriched barrier at that boundary separated the intrafollicular program from an effector-rich interfollicular compartment. Within follicles, CD14-high follicular dendritic cells defined an activated stromal niche that supported tumor B cell proliferation and predicted shorter progression-free and overall survival. Across patients, per-cell CD14 intensity was the strongest predictor of progression, remaining prognostic independently of FLIPI, grade, and stage. VISTA, not PD-L1, dominated checkpoint expression across all myeloid subtypes in both follicular and interfollicular zones, and was further amplified on M2 macrophages in patients carrying EP300 mutations. S100A9+ MDSC-like cells were the strongest myeloid predictor of histologic transformation. Agent-based modeling of this architecture predicted synergistic tumor clearance when anti-VISTA was combined with a CD20-CD3 bispecific antibody. These findings establish that FL uses tissue architecture as an immune evasion mechanism and identify VISTA and CD14-high follicular dendritic cells as candidate therapeutic targets.