Follicular Dendritic Cells Represent a Therapeutic Vulnerability in Early Follicular Lymphoma

Follicular lymphomas (FLs) arise from germinal center (GC) B cells and contain a rich tumor microenvironment (TME) including CD4+ and CD8+ T cells, macrophages, and lymphoid stromal cells, among which follicular dendritic cells (FDCs) are particularly abundant. FDCs interact with GC B cells through antigen presentation, secretion of BAFF, which binds to BAFFR to induce trophic signals, and secretion of CXCL13, which draws B cells into GCs via CXCR5. While the role of FDCs in FL is not fully understood, BAFFR expression has been associated with worse outcomes in diffuse large B-cell lymphoma. We hypothesized that FDCs 1) play a critical role in FL, primarily through BAFF signaling, 2) represent a therapeutic target in FL, and 3) are most amenable to targeting as a form of early intervention therapy for FL. We profiled the FL TME of 151 patient biopsies at the spatial level using imaging mass cytometry (IMC) and found that FDCs were highly prevalent and in close proximity to FL B cells. We previously showed that FDCs are especially abundant in both human and murine EZH2Y641F gain-of-function mutant FLs. To determine the functional relevance of these FDCs and the potential relevance of BAFF, we administered anti-BAFF blocking antibody to immunized mice bearing 50% WT and 50% mutant EZH2 B cells. BAFF blockade caused significantly greater depletion of EZH2Y641F GC B cells relative to WT (p<0.05), documenting a critical role for FDCs and BAFF in EZH2 mutant GC B cells. We generated and credentialed a bona fide FL mouse model, driven by GC-specific expression of BCL2 and EZH2Y641F. These EZH2/BCL2 mice develop lymphoid hyperplasia at 5 months and FL at 8 months. To investigate the changing composition of the TME in FL, we immunized a cohort of 25 EZH2/BCL2 mice and sacrificed 5 mice at 5 time points between 6 and 11 months. We extracted RNA from spleen containing lymphoma cells and the entire TME and performed qPCR on 93 genes, including cytokines and chemokines involved in GC intercellular signaling. BAFF transcript abundance was increased in EZH2/BCL2 relative to WT mice at all timepoints (p<0.05), supporting BAFF as potentially biologically relevant in FL. Given the relevance of the BAFF-BAFFR axis and mutant EZH2 dependency on FDCs, we next investigated the effects of BAFF and EZH2 inhibition on FL incidence and TME composition. We treated 40 immunized EZH2/BCL2 mice biweekly with anti-BAFF or IgG control beginning at 6 months. Mice also received 3 weeks of tazemetostat (taz), an EZH2 inhibitor approved in FL, or vehicle (veh) before sacrifice at 7 months (recapitulating early FL) and 11 months (late FL) (n=20 per timepoint). We analyzed splenic tissues by histology, flow cytometry, and immunofluorescence (IF) imaging. Combined anti-BAFF + taz, and to a lesser extend anti-BAFF, delayed the onset and progression of FL. Anti-BAFF increased the recruitment of CD4+ and CD8+ T cells into follicular areas in both early (p<0.001) and late (p<0.05) timepoints. This was enhanced by taz at the late timepoint (1.5-fold, p<0.05). IF showed that BAFF blockade decreased FDC contacts with FL B cells (1.9-fold) and T cells (2.6-fold) at the early timepoint. In contrast, at the late timepoint, anti-BAFF increased FDC contacts with FL B cells (1.7-fold) but not T cells. Similarly, anti-BAFF decreased CXCL13+ FDCs at the early timepoint (1.7-fold) but increased CXCL13+ FDCs at the late timepoint (0.6-fold). These findings suggest that BAFF inhibition increases T cell involvement in FL and decreases FL incidence, though these effects are later reversed, potentially through compensatory resistance mechanisms or neutralizing antibodies against anti-BAFF. Notably, the presence of CXCL13+ FDCs was linked to inferior PFS in our cohort of FL patients profiled by IMC (p<0.001) and CXCL13 transcripts were progressively increased in our EZH2/BCL2 mice analyzed at various timepoints as compared to WT. CXCL13 expression may highlight active FDCs, which decrease at the early timepoint with BAFF inhibition and later recur as FL progresses. Overall, we identify FDCs as a therapeutic target in FL and highlight the additive effects of EZH2 inhibition. We further establish a critical treatment window early in FL at which point BAFF and EZH2 inhibition increase T cell involvement within the TME and prevent FL formation. These findings reveal a promising strategy for treating FL early in its disease course and potentially for enhancing T cell-based immunotherapies.

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