A germinal center–associated microenvironmental signature reflects malignant phenotype and outcome of DLBCL

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.

Lymphoma Microenvironment in DLBCL and PTCL-NOS: the key to uncovering heterogeneity and the potential for stratification

“…Interestingly, this prognostic model was inversely correlated with genomic alterations, gene expression, and phenotypes such as doubleexpressor lymphoma, which are known to be associated with a poor prognosis. 85 Collectively, these data suggest that the LME signature reflects the multifaceted signatures of tumor cells themselves that explain the malignant activity of DLBCL. This opens up the possibility of developing a simple prognostic tool that reflects information that would be known through various omics tests such as IHC, FISH, genomic mutation, and gene expression profiling.…”

“…83,84 Recently, our group exploited the nCounter system to semi-comprehensively screen genes related to tumor cells and microenvironment-related genes, in combination with whole transcriptome screening by RNA-seq, to determine the prognostic genes in DLBCL. 85 As a result, many microenvironment-related genes, especially those of follicular T cells (Tf), dendritic cells/macrophages (DC/Mφ), and stromal cell lineages, were extracted as prognostic genes rather than tumor cell-related genes. A simple prognostic score, which we called the DLBCL Microenvironment Signature (DMS) score, was generated using the most powerful prognostic genes among each LME component: ICOS (Tf marker), CD11c/ITGAX (DC/Mφ marker), and FGFR1 (stromal marker).…”

“…Our groups recently performed gene expression profiling using a similar approach to that of the DLBCL study described above. 85 To identify the gene signatures which can effectively stratify otherwise heterogeneous PTCL-NOS cases, we evaluated the expression levels of both tumor and microenvironment immune cell-related genes in 68 newly diagnosed PTCL-NOS cases treated with CHOP-based regimens using the nCounter system. 100 In the Pearsoncorrelation matrix, the distinct clusters of microenvironment genes, including B cells, macrophages, and DC/mast cells, while clusters of T cell-related genes were not evident.…”

“…In fact, most of the DC signature cases were non-lymph node lesions such as skin, gastrointestinal tract, and pharynx. 85,100 The prognosis for the B cell and DC-poor group (non-BD), which accounts for >40% of PTCL-NOS cases, is extremely poor, and more than half of these cases have a macrophage signature. Interestingly, tumor-infiltrating macrophages expressed immune-checkpoint molecules, such as PD-L1/L2 and IDO1, 100 indicating that macrophages expressing PD-L1 may contribute to the poor prognosis.…”

Tumor Purity-Related Genes for Predicting the Prognosis and Drug Sensitivity of DLBCL Patients

“…Moreover, the comprehensive investigation of non-immune cell components in the TME is still lacking. Previous research on stroma in DLBCL has predominantly indicated that a higher quantity of extracellular matrix is associated with a more favorable prognosis, while increased vascular density is associated with poorer prognosis [9]. Furthermore, higher stromal scores have been associated with an improved prognosis in DLBCL patients [10].…”