Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue

S. Ciavarella, M.C. Vegliante, M. Fabbri, S. De Summa, F. Melle, G. Motta, V. De Iuliis, G. Opinto, A. Enjuanes, S. Rega, A. Gulino, C. Agostinelli, A. Scattone, S. Tommasi, A. Mangia, F. Mele, G. Simone, A.F. Zito, G. Ingravallo, U. VitoloA. Chiappella, C. Tarella, A.M. Gianni, A. Rambaldi, P.L. Zinzani, B. Casadei, E. Derenzini, G. Loseto, A. Pileri, V. Tabanelli, Stefano Fiori, A. Rivas-Delgado, A. López-Guillermo, T. Venesio, A. Sapino, E. Campo, C. Tripodo, A. Guarini, S.A. Pileri

Research output: Contribution to journalArticlepeer-review


Background: Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.
Original languageEnglish
Pages (from-to)2363-2370
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Issue number12
Publication statusPublished - 2018


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