{"doi":"10.1172/jci187371","title":"Aggressive B cell lymphomas retain ATR-dependent determinants of T cell exclusion from the germinal center dark zone","abstract":"The germinal center (GC) dark zone (DZ) and light zone represent distinct anatomical regions in lymphoid tissue where B cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse large B cell lymphomas (DLBCLs) with DZ-like gene expression profiles exhibit poor outcomes, though the reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T cells, prompting exploration of whether T cell paucity contributes to DZ-like DLBCL. We used spatial transcriptomic approaches to achieve higher resolution of T cell spatial heterogeneity in the GC and to derive potential pathways that underlie T cell exclusion. We showed that T cell exclusion from the DZ was linked to DNA damage response (DDR) and chromatin compaction molecular features characterizing the spatial DZ signature, and that these programs were independent of activation-induced cytidine deaminase (AID) activity. As ATR is a key regulator of DDR, we tested its role in the T cell inhibitory DZ transcriptional imprint. ATR inhibition reversed not only the DZ transcriptional signature, but also DZ T cell exclusion in DZ-like DLBCL in vitro microfluidic models and in in vivo samples of murine lymphoid tissue. These findings highlight that ATR activity underpins a physiological scenario of immune silencing. ATR inhibition may reverse the immune-silent state and enhance T cell-based immunotherapy in aggressive lymphomas with GC DZ-like characteristics.","journal":"Journal of Clinical Investigation","year":2025,"id":545426,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":337167,"name":"Giorgio Bertolazzi","orcid":"0000-0001-7328-9675","position":1,"is_corresponding":false},{"id":1335472,"name":"Allison Chan","orcid":"0000-0001-5657-0270","position":2,"is_corresponding":false},{"id":1436687,"name":"Giovanni Medico","orcid":null,"position":3,"is_corresponding":false},{"id":1335473,"name":"Giulia Bastianello","orcid":"0000-0002-9533-1931","position":4,"is_corresponding":false},{"id":1335471,"name":"Gaia Morello","orcid":"0000-0003-3400-8732","position":5,"is_corresponding":false},{"id":1243155,"name":"Daniel Paysan","orcid":"0000-0003-4995-7527","position":6,"is_corresponding":false},{"id":1436688,"name":"Clemence Lai","orcid":null,"position":7,"is_corresponding":false},{"id":1436219,"name":"Hong Liang","orcid":"0000-0002-1979-2509","position":8,"is_corresponding":false},{"id":1436689,"name":"Girija Shenoy","orcid":null,"position":9,"is_corresponding":false},{"id":827905,"name":"Patrick Jaynes","orcid":"0000-0002-3297-8674","position":10,"is_corresponding":false},{"id":318683,"name":"Giovanna Schiavoni","orcid":"0000-0001-9135-0556","position":11,"is_corresponding":false},{"id":318679,"name":"Fabrizio Mattei","orcid":"0000-0002-5357-7773","position":12,"is_corresponding":false},{"id":1335474,"name":"Silvia Piconese","orcid":"0000-0002-9685-5227","position":13,"is_corresponding":false},{"id":318555,"name":"María V. 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