Spatial and multi-omic profiling reveals pericyte-derived CCL19 as a key prognostic factor in CNS lymphoma.

Biological mechanisms underlying clinical heterogeneity in central nervous system lymphoma (CNSL) are largely unknown. While previous studies suggest the chemokine CLL19 as a crucial factor for the formation of CNSL in murine models, its role in human disease remains elusive. Here, we performed in-depth genetic and transcriptomic profiling of 82 CNSL specimens and identified distinct genetic aberrations and tumor cell compositions in lymphomas with high CCL19 expression, both of which were associated with immunosuppressive and anti-apoptotic signatures. CCL19 levels varied widely across CNSL patients. High CCL19 expression was significantly and independently associated with inferior progression-free and overall survival. Spatial and single-nucleus analyses as well as immunohistochemistry revealed pericytes within vessel-rich areas as the predominant source of CCL19, accompanied by significant co-localization of CCL19 with its primary receptor CCR7 that was enriched in plasmablast-like malignant B cells, as well as dendritic cells, NK cells, and CD4+ T cells. Collectively, our study identified pericyte-derived CCL19 as a novel prognostic marker in CNSL that is associated with unfavorable genetic aberrations and modifications of the immune landscape towards a resting tumor microenvironment. Spatial CCR7 co-localization suggests avenues for future therapeutic strategies targeting the CCL19-CCR7 axis.