Clonal and spatial architecture of primary central nervous system lymphoma – LOCimm

Primary central nervous system lymphoma (PCNSL), a rare subtype of extranodal non-Hodgkin’s lymphoma (NHL), is defined as a diffuse large B-cell lymphoma (DLBCL) arising exclusively within the brain, spinal cord, leptomeninges, or eye according to the new WHO Classification of Tumors of the Central Nervous System. PCNSL have distinct and distinguishing characteristics from nodal DLBCLs. Because of their rarity, molecular characterization has been confined to a small number of samples, and the involvement of the tumor microenvironment (TME) in disease progression and/or therapy response has remained unknown.
Our central hypothesis is that variations in tumor cell states and TME organization play a role in lymphomagenesis and progression. We believe that distinct TME contribute to intra- and intertumoral heterogeneity across PCNSL, and that these TME can be targeted in the future.This proposal includes three complementary and multidisciplinary aims to i) characterize the immune landscape of PCNSL at single-cell level, ii) improve prognostic and predictive markers, and iii) propose mechanistic biological understanding of the different PCNSL molecular subtypes. To this end, we will use single-cell RNA transcriptome analysis, the analysis of whole-slide imaging (WSI) of 300 PCNSL to assess the role of spatial immune distribution in the clinical outcome of these rare entities using the already available patient’s data from a French phase III clinical trial, BLOCAGE (clinical trials reference NCT02313389). Finally, we will propose a proof-of-concept study to analyze the geometric and biophysical properties of B cells associated to each molecular group of PCNSL using FACS selected B cells from fresh tumors and blood samples.
The analysis of TME of PCNSL using a large number of samples may facilitate the understanding and provide a comprehensive description of the heterogeneity within this rare subytpe of lymphomas.