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

TitleGerminal Center Dark Zone harbors ATR-dependent determinants of T-cell exclusion that are also identified in aggressive lymphoma.
Publication TypeJournal Article
Year of Publication2024
AuthorsCancila V, Morello G, Bertolazzi G, Chan ASi-Yu, Bastianello G, Paysan D, Jaynes PWilliam, Schiavoni G, Mattei F, Piconese S, Revuelta MV, Noto F, De Ninno A, Cammarata I, Pagni F, Venkatachalapathy S, Sangaletti S, Di Napoli A, Vacca D, Lonardi S, Lorenzi L, Ferreri AJM, Belmonte B, Varano G, Colombo MPaolo, Bicciato S, Inghirami G, Cerchietti L, Ponzoni M, Zappasodi R, Facchetti F, Foiani M, Casola S, Jeyasekharan AD, Tripodo C
JournalRes Sq
Date Published2024 Mar 18
ISSN2693-5015
Abstract

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. The DZ and LZ differ significantly in their immune composition despite the lack of a physical barrier, yet the determinants of this polarization are 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 that underlie DZ T-cell exclusion. 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 establishing 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.

DOI10.21203/rs.3.rs-4093618/v1
Alternate JournalRes Sq
PubMed ID38562878
PubMed Central IDPMC10984086
Grant ListR01 CA242069 / CA / NCI NIH HHS / United States