Abstract IA05: Microenvironmental signatures reveal biologic and clinical subtypes of diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease almost invariably treated with combinatorial chemoimmunotherapy resulting in a ~65% cure rate in first line. Further improvement of treatment outcome relies on elucidating the biology that underlies the clinical behavior of this heterogenous disease. Transcriptomic and genetic characterization of DLBCL have increased our understanding of its pathogenesis and provided potential novel therapeutic targets. Over the past few years, the role of the microenvironment in DLBCL biology has been increasingly recognized. A guiding framework is necessary to effectively and safely translate research evidence into clinical practice. Towards this goal, we characterized the DLBCL microenvironment based on the transcriptional footprint of microenvironment cells and processes in a large cohort of patients. We first developed transcriptional signatures reflecting distinct cellular subtypes of the microenvironment, biologic processes, and canonical signaling pathway activation. We then used these signatures to virtually reconstruct the lymphoma microenvironment (LME) by applying an unsupervised community detection algorithm in 4,656 DLBCL cases. As a result, we described four classes of LMEs that reflect distinct enrichment of associated signatures. 1. “Germinal center-like” (GC-like) due to the presence of signatures from cell types commonly found in germinal centers including follicular dendritic cells, lymphatic endothelial cells, total T cells, and several CD4+ T-cell subpopulations. 2. “Mesenchymal” (MS) for the abundance of signatures from stromal cells such as cancer-associated fibroblasts, fibroblastic reticular cells, vascular endothelial cells, and extracellular matrix pathways. The MS-LME class was enriched in mutations affecting antigen presentation. These lymphomas also presented with high activity of the TGFB/SMAD and HIF pathways, previously associated with favorable prognosis in DLBCL. 3. “Inflammatory” (IN) for the presence of signatures from macrophages, neutrophils, NK cells, and cytotoxic T cells. The IN-LME class was enriched for immune suppressive/pro-lymphoma cytokines, expression of the immune checkpoint molecules PD-L1 and IDO1, and higher activity of the NF-kB, JAK/STAT, and TNF signaling pathways. 4. A “depleted” (DP) form that, contrasting with the other LMEs, was characterized by an overall lower presence of microenvironment-derived signatures. We analyzed the association of LME classes with overall survival (OS) and progression-free survival (PFS) in patient cohorts of, respectively, 2,646 and 2,189 DLBCLs treated with rituximab-based chemoimmunotherapy. Analysis of OS by LME indicated significant differences in prognosis from better to poor as follows: GC-like, MS (p =0.03, vs. GC-like), IN (p = 0.006, vs. MS), and DP (p = 0.008, vs. IN) LMEs, whereas GC-like and MS have similarly favorable PFS curves (p = 0.9) followed by IN (p Citation Format: Leandro Cerchietti. Microenvironmental signatures reveal biologic and clinical subtypes of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA05.