Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma

Abstract

Lymphoid hyperplasia of gastric mucosa associated with Helicobacter pylori (HP) infection represents a preneoplastic condition of the mucosa associated lymphoid tissue (MALT), which may evolve to a B-cell lymphoma. While it is well established that the initial neoplastic proliferation of B cells is antigen-driven and dependent on the helper activity of HP-specific T cells, it needs to be elucidated which cytokine or soluble factor(s) promote Bcell activation and lymphomagenesis. Herein, we originally report that gastric MALT lymphoma express high levels of a proliferation inducing ligand (APRIL), a novel cytokine crucial in sustaining B-cell proliferation. By immunohistochemistry, we demonstrate that APRIL is produced almost exclusively by gastric lymphomainfiltrating macrophages located in close proximity to neoplastic B cells. We also show that macrophages produce APRIL on direct stimulation with both HP and HP-specific T cells. Collectively, our results represent the first evidence for an involvement of APRIL in gastric MALT lymphoma development in HP-infected patients. (Blood. 2011;117(24):6612-6616) IntroductionHelicobacter pylori (HP) colonizes the human gastric mucosa and triggers a strong local inflammatory response. 1 Chronic inflammation because of the persistence of HP infection can give rise to organized lymphoid tissue in the gastric mucosa, the so-called mucosa-associated lymphoid tissue (MALT) that, in a small subset of individuals, can ultimately progress to low-grade gastric B-cell lymphoma of MALT type. 2 The current model of MALT lymphoma genesis assumes that one or more neoplastic clones, displaying characteristics of marginal zone B cells, originate from the organized MALT, colonize and replace the original follicles and eventually destroy the gastric glands to form lympho-epithelial lesions. 3 Although MALT lymphoma usually grows slowly and has a low propensity to spread, a small percentage of cases undergo high-grade transformation. It is generally accepted that, in early stages of gastric lymphoma development, neoplastic growth is both antigen-driven and dependent of the helper activity of T cells specific for HP. 2,4 The fact that the eradication of the bacterium leads to regression of the lymphoma, especially in its early stages, is consistent with such a postulate. 5,6 However, less is known about the role of the host immune response in MALT lymphoma pathogenesis.A proliferation inducing ligand (APRIL) is one of the most recently cloned members of the tumor necrosis factor (TNF) family 7-10 expressed by a variety of immune cells including neutrophils, monocytes, macrophages, dendritic cells, and T cells, but also epithelial cells and tumor cells. By binding to its BCMA and TACI receptors, APRIL promotes survival and proliferation of B cells as well as their differentiation to plasma cells. As recently reported, APRIL-transgenic mice develops lymphoid malignancies originating from peritoneal B-1 B cells. 11 In addition, not only APRIL is expressed in a wide array of B-cell malignancies,...

Cytokine BAFF Released byHelicobacter pylori–Infected Macrophages Triggers the Th17 Response in Human Chronic Gastritis

“…Different studies have demonstrated that the activation of BAFF and APRIL signal transduction pathways may contribute to both H. pylori-independent and H. pylori-dependent growth of gastric MALT lymphomas (41,42). Our investigation stemmed from the evidence, obtained in two different models of autoimmune disease, that BAFF is a cytokine crucial in promoting the expansion of Th17 cells (11,12).…”

Delivery of chemotherapeutic drugs in tumour cell-derived microparticles

“…Furthermore, regardless of the homology between MPs and tumour cells, it is inevitable that MPs will be taken up by phagocytes, such as macrophages 15,34,35 . This, however, might actually be beneficial to cancer treatment, because tumour-associated macrophages have very important roles in tumour development by promoting neoangiogenesis, remodelling tumour microenvironment and dampening the immune response to tumours [36][37][38][39] . In this study, we observed that peritoneal macrophages took up drug-packaging MPs and then died.…”

Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue—from (auto)antigen driven selection to the activation of NF-κB signaling

“…This implies that ROS participate in the formation of the "acquired lymphoid tissue". Another component of the "acquired lymphoid tissue" is the lymphoma-associated macrophages that release a proliferation inducing ligand (APRIL), which promotes the progression of Hp-associated MALT lymphoma [42,43]. With the help of Hp-specific T-cells, this phenomenon could be further amplified and prolonged [43].…”

“…Another component of the "acquired lymphoid tissue" is the lymphoma-associated macrophages that release a proliferation inducing ligand (APRIL), which promotes the progression of Hp-associated MALT lymphoma [42,43]. With the help of Hp-specific T-cells, this phenomenon could be further amplified and prolonged [43]. Finally, the up-regulation of certain chemokines, such as C-C chemokine receptor type 7 (CCR7), CXC chemokine receptor (CXCR)3, CXCR7 and Chemokine C-X-C motif ligand 12 (CXCL12), as well the down-regulation of CXCR4, are found in gastric MALT lymphoma, which indicates that chemokines also play an important role in disease progression (Figure 1) [44,45].…”