Analysis of Cellular Heterogeneity in Immune Microenvironment of Primary Central Nervous System Lymphoma by Single-Cell Sequencing

Abstract

BackgroundPrimary central nervous system lymphoma (PCNSL) is characterized by a lack of specificity and poor prognosis. Further understanding of the tumor heterogeneity and molecular phenotype of PCNSL is of great significance for improving the diagnosis and treatment of this disease.MethodsTo explore the distinct phenotypic states of PCNSL, transcriptome-wide single-cell RNA sequencing was performed on 34,851 PCNSL cells from patients. The cell types, heterogeneity, and gene subset enrichment of PCNSL were identified. A comparison of the PCNSL cells with 21,250 normal human fetal brain (nHFB) cells was further analyzed to reveal the differences between PCNSL and normal sample.ResultsSix cell populations were mainly identified in the PCNSL tissue, including four types of immune cells—B cell, T cell, macrophage and dendritic cell—and two types of stromal cells: oligodendrocyte and meningeal cell. There are significant cellular interactions between B cells and several other cells. Three subpopulations of B cells indicating diffident functions were identified, as well as a small number of plasma cells. Different subtypes of T cells and dendritic cells also showed significant heterogeneity. It should be noted that, compared with normal, the gene expression and immune function of macrophages in PCNSL were significantly downregulated, which may be another important feature of PCNSL in addition to B cell lesions and may be a potential target for PCNSL therapy.

Leveraging the CSF proteome toward minimally-invasive diagnostics and biological characterization of brain malignancies

“…To explore the biology of these biomarkers, we assessed their transcriptional profiles using publicly-available single cell transcriptomic (scRNAseq) profiles of GBM, 28 lung adenocarcinoma BM, 29 and CNSL ( Fig S7 ). 30 In GBM scRNAseq data, GAP43 expression was largely restricted to GBM cells, limited in lymphoid and myeloid cells, and entirely absent in BM and CNSL cells. TFF3 was exclusively expressed in BM.…”

“…Proteomic data from Schmid et al was obtained from ProteomeXchange (ID: PXD021984 ); 16 Bader et al from ProteomeXchange (ID: PXD016278 ); 22 Bereman et al from Dataset 1 file of electronic supplementary material of original publication; 23 and Stoop et al from Supporting Information File 2 of original publication. 24 Single cell RNA seq data from Wei et al (2021) was obtained from Gene Expression Omnibus (GEO; accession number GSE181304 ); 30 Neftel et al (2019) from GEO (accession number GSE131928 ); 28 and Kim et al (2020) from GEO (accession number GSE131907 ). 29…”

“…Public scRNAseq profiles of GBM ( left column ), LUAD brain metastases ( middle column ), and CNSL ( right column ) were annotated according to original reports 28–30 ( A ) and expression of SOD2 ( B ), GAP43 ( C ), TFF3 ( D ), PZP ( E ), CACNA2D2 ( F ), and CTSZ ( G ) were visualized using UMAPs ( insets ) for cell-level profiles, and bar plots for aggregate cell-type-specific expression. Bolded cell labels indicate neoplastic populations.…”

Specific KIR-HLA genotypes predict outcomes of refractory or recurrent primary central nervous system lymphoma

“…The sample size is small in this study, so the conclusion needs to be further con rmed by a larger sample size in future. Interestingly, only four types of immune cells-B cells, T cells, macrophages and dentritic cells has been identi ed in the microenvironment of PCNSL up to now [43]. If NK cells did not reside in the tumor microenvironment, how could they exert anti-tumor effect?…”

Location, location, location: mapping the lymphoma tumor microenvironment using spatial transcriptomics

“…Wei et al. ( 74 ) performed scRNAseq on fresh PCNSL tissue and demonstrated an immune rich milieu including plentiful infiltrating B cells, T cells, macrophages and dendritic cell populations; single cell analysis allowed greater resolution to determine the sub-clusters of each immune cell type and to infer functional heterogeneity, for example highlighting the potential importance of CD74 in regulating communication between PCNSL cells and T cells, macrophages and dendritic cells.…”