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Interaction between stromal cells and GCB-DLBCL cells promotes the tumor cell survival through CD40-KDM6B-NF-B axis

ABSTRACT: Germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is one of the most common subtypes of B-cell non-Hodgkin lymphoma. The tumor microenvironment (TME) is responsible for therapy resistance and relapse in GCB-DLBCL, while most studies have focused on targeting tumor cells instead of the TME. Stromal cells are the main component of the TME in GCB-DLBCL. How stromal cells interact with GCB-DLBCL tumor cells and protect GCB-DLBCL from cell death remain elusive. Here we reported that a CD40/RANK pathway-mediated positive feedback loop mediated the interaction of stromal cells and GCB-DLBCL to enhance the survival of GCB-DLBCL tumor cells. The viability of primary GCB-DLBCL patient-derived xenograft tumor cells was increased when they were cocultured with different tissue-derived stromal cells. We demonstrated that stromal cells promoted tumor cell survival not only through excreted cytokines but also depending more on direct contact. Furthermore, CD40 ligand (CD40L) expressed on stromal cells activated CD40 signaling in tumor cells, protecting tumor cells from apoptosis and upregulating RANK ligand (RANKL). RANK activation by RANKL in tumor cells enhanced the expression of CD40L and BAFF in stromal cells, both of which in turn promoted tumor cell survival through activating canonical and noncanonical NF-B signaling. In addition, CD40 activation upregulated the expression of KDM6B, and KDM6B further mediated the activation of canonical and noncanonical NF-B signaling, the downstream signaling pathways of the CD40 activation, all leading to tumor cell survival. These results further suggest that CD40-KDM6B-NF-B axis serve as a potential target for GCB-DLBCL therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202370 | GEO | 2022/05/09

REPOSITORIES: GEO

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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center B cell-like (GCB) and activated B cell like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations at multiple genes, including negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB responses, is the most commonly affected one, with ~30% of the patients displaying biallelic inactivation by mutations and/or deletions, suggesting a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses. We show that most ABC-DLBCL and a smaller fraction of GCB-DLBCL display genetic lesions affecting multiple NFkB pathway genes, with A20 representing the most frequently mutated gene Experiment Overall Design: DLBCL biopsies from 73 patients were collected from the archives of the Departments of Pathology at Columbia University and Weill Cornell Medical College. Total RNA was extracted from frozen tumor biopsies and processed according to Affymetrix standard protocols. Purified tonsillar geminal center cells (centroblasts and centrocytes, 5 samples each from different individuals) were purified by magnetic cell separation as described in Klein et al, PNAS 2003.

Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human Î²-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 Î², which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (GroÎ±), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither Î²-cell death and did not enhanced TNF-Î± mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and Î²-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in Î²-cells, induces secretion of diabetogenic cytokines IFNÎ³ and TNF-Î±. Furthermore, incubation of islets containing ductal cells with CD40L decreased Î²-cells viability as assessed by measurement of their mitochondrial membrane potential Experiment Overall Design: We isolated islet cells from three patients. Part of islet cells from each patient has been treated with CD40L. We compared gene expression in treated cells vs untreated for each patient using dye-swap.

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Interaction between stromal cells and GCB-DLBCL cells promotes the tumor cell survival through CD40-KDM6B-NF-B axis

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