Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. SIGNIFICANCE: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.

Automated summary

In this study, a transcriptomic analysis of the microenvironment of DLBCL was conducted, revealing four major lymphoma microenvironment categories associated with distinct biological aberrations and clinical behavior. This research also identified genetic and epigenetic mechanisms used by cancer cells to evade microenvironmental constraints and suggested the use of DNA hypomethylating agents in selected DLBCL patients. Additionally, new therapeutic vulnerabilities in the extracellular matrix composition were uncovered, providing potential targets for decreasing DLBCL proliferation in preclinical models.