{"doi":"10.1002/hon.70093_84","title":"84 | DISRUPTING FOLLICULAR DENDRITIC CELL INTERACTIONS AND EPIGENETIC REGULATION TO PREVENT FOLLICULAR LYMPHOMA PROGRESSION","abstract":"Introduction: Follicular lymphoma (FL) arises from germinal center (GC) B cells within a complex tumor microenvironment (TME), including follicular dendritic cells (FDCs), which support FL B cells via antigen presentation, CXCL13 secretion, and BAFF-BAFFR signaling. While BAFFR expression correlates with poor outcomes in diffuse large B-cell lymphoma, its role in FL remains unclear. We previously found FDCs to be enriched in EZH2Y641F-mutant FL and a murine model of pre-malignant EZH2Y641F B cells. We hypothesized that FDCs contribute to FL progression via BAFF signaling, making them a potential therapeutic target. Methods and Results: Imaging mass cytometry of 151 FL patient biopsies revealed abundant FDCs, with CXCL13+ FDCs correlating with inferior PFS (p < 0.001). To assess functional relevance, we blocked BAFF in chimeric mice containing WT and EZH2Y641F GC B cells, which led to preferential depletion of EZH2Y641F GC B cells (p < 0.05), confirming BAFF’s role in pre-malignant niches. To examine disease progression, we used our FL mouse model with GC-specific BCL2 and EZH2Y641F expression, characterized by lymphoid hyperplasia at 5 months and FL by 8 months. FDC-related cytokines BAFF and CXCL13, and CD21+ FDCs increased early in disease progression, as measured by qPCR and immunofluorescence (IF) imaging (p < 0.01). In FL patient-derived co-cultures, BAFF enhanced FL B cell proliferation, which was inhibited by BAFF blockade (belimumab). Ex vivo cultures of primary murine FL B cells further confirmed that BAFF stimulation activated the noncanonical NFκB signaling pathway, improving viability, particularly in EZH2Y641F cells. To test therapeutic potential, we treated EZH2Y641F/BCL2 mice with anti-BAFF ± tazemetostat (EZH2 inhibitor) at early (6 months, n = 40) and late (8 months, n = 40) disease stages. Anti-BAFF delayed FL onset and progression, reduced B cell burden (p < 0.0001), and increased T cell recruitment (p < 0.001), with tazemetostat enhancing effects in late disease. IF imaging showed reduced CXCL13+ FDCs and FDC-B cell interactions early, but compensatory FDC expansion at later stages. Conclusions: FDCs play a pivotal role in FL progression, particularly in early disease. BAFF inhibition disrupts FDC-B cell interactions, enhances T cell recruitment, and reduces FL incidence, with effects amplified by EZH2 inhibition. These findings highlight a critical therapeutic window in early FL where targeting FDCs and epigenetic modulation could prevent or reverse disease progression by altering the TME. These findings reveal a promising strategy for treating FL early in its disease course and potentially for enhancing T cell-based immunotherapies. Research funding declaration: NIH NCI R01 CA270245, LLS TRP 6641-22, LLS TRP 6679-24, FLF CURE FL 224362, LRF FL PRG 226504, Gilead Sciences Research Scholars Program GSI 231647-01 Keywords: microenvironment; combination therapies; indolent non-Hodgkin lymphoma No potential sources of conflict of interest.","journal":"Hematological Oncology","year":2025,"id":568584,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"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":534239,"name":"J. Yan","orcid":null,"position":1,"is_corresponding":false},{"id":470303,"name":"Ioannis Karagiannidis","orcid":"0000-0001-5850-957X","position":2,"is_corresponding":false},{"id":1473448,"name":"Do McNally","orcid":null,"position":3,"is_corresponding":false},{"id":46686,"name":"S. Lee","orcid":"0000-0002-6742-6677","position":4,"is_corresponding":false},{"id":1472870,"name":"Baptiste Brauge","orcid":"0000-0003-1544-5419","position":5,"is_corresponding":false},{"id":1473449,"name":"HA Martin","orcid":null,"position":6,"is_corresponding":false},{"id":65087,"name":"Karin Tarte","orcid":"0000-0002-6809-917X","position":7,"is_corresponding":false},{"id":251430,"name":"Abner Louissaint","orcid":"0000-0001-6707-917X","position":8,"is_corresponding":false},{"id":308650,"name":"Amy Chadburn","orcid":"0000-0002-9499-8638","position":9,"is_corresponding":false},{"id":1171524,"name":"Madhu M. Ouseph","orcid":"0000-0002-3422-1675","position":10,"is_corresponding":false},{"id":106831,"name":"David W. Scott","orcid":"0000-0002-0435-5947","position":11,"is_corresponding":false},{"id":237422,"name":"Ari Melnick","orcid":"0000-0002-8074-2287","position":12,"is_corresponding":false},{"id":237414,"name":"Wendy Béguelin","orcid":"0000-0002-4894-9229","position":13,"is_corresponding":false},{"id":1473447,"name":"C Gribbin","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:56:52.212268Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}