Germinal Center Dark Zone harbors ATR-dependent determinants of T-cell exclusion that are also identified in aggressive lymphoma – Visium_FFPE_Spatial_Trasciptomics_project

The germinal center (GC) dark zone (DZ) and light zone (LZ) regions spatially separate expansion and diversification from selection of antigen-specific B-cells to ensure antibody affinity maturation and B cell memory. How GC polarity is established is poorly understood. This study provides novel insights into signals controlling asymmetric T-cell distribution between DZ and LZ regions. We identify spatially-resolved DNA damage response and chromatin compaction molecular features precluding DZ T-cell infiltration. The DZ spatial transcriptional signature linked to T-cell immune evasion clustered aggressive Diffuse Large B-cell Lymphomas (DLBCL) for differential T cell infiltration. We reveal the dependence of the DZ transcriptional core signature on the ATR kinase and dissect its role in restraining inflammatory responses contributing to estabslish an immune-repulsive imprint in DLBCL. These insights may guide ATR-focused treatment strategies bolstering immunotherapy in tumors marked by DZ transcriptional and chromatin-associated features. Whole-genome transcriptomic profiling was performed on formalin-fixed tissue sections of mouse FFPE mesenteric lymph nodes from two samples: one with a knocked Aicda gene (B6.129P2-Aicdatm1(cre)Mnz/J, Jackson, RRID no 007770) and the other under wild-type conditions for Aicda gene (B6N;129-Ilktm1Star/J, Jackson, RRID no 023310). grant ID : *22145* grant title: *Linking genetic evolution, stromal and immune contextures to unravel tumor heterogeneity in aggressive B-cell lymphomas* name of the funding source:* A.I.R.C. (Associazione Italiana Ricerca Cancro) *