Poster Presentation 32nd Lorne Cancer 2020

All roads lead to Rome: CD40-CD40L and BAFF/APRIL-TACI signaling pathways as potential therapeutic targets in Helicobacter-induced gastric MALT lymphoma (#373)

Le Ying 1 2 , Michelle Chonwerawong 2 , Phoebe Liu 3 , Pascal Schneider 4 , Richard L. Ferrero 1 2 5
  1. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
  2. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  3. Trinity College, University of Toronto, Toronto, Canada
  4. Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
  5. Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia

Gastric mucosa-associated lymphoid tissue (gMALT) lymphoma is a form of lymphoma that originates from B cells in the stomach. Many studies have shown that this disease is highly associated with chronic Helicobacter pylori (H. pylori) infection. The first-line therapy for gMALT lymphoma is the administration of antibiotics against H. pylori infection. However, treatment options are limited for those subjects carrying antimicrobial-resistant strains or in whom the disease has advanced to late stage. Thus, there is a need to develop new approaches for the treatment of gMALT lymphoma.

Our laboratory has generated a novel mouse model which exhibits MALT formation in the stomach at 3 months post Helicobacter infection. These mice have a myeloid cell-specific deletion in the gene encoding NOD-like receptor family CARD domain containing 5 (Nlrc5). Using this model, we investigated the roles of T cell-dependent and independent signaling pathways, respectively, in Helicobacter-induced gastric B cell proliferation by therapeutically targeting either CD40-CD40L interactions or those between cyclophilin ligand interactor (TACI)-Ig and the soluble B cell factors, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Here, we report that chronic Helicobacter infection in Nlrc5KO mice treated with either anti-CD40L antibody or TACI-Ig protein developed significantly fewer B cell follicles, less infiltration of CD4+ T cells and dendritic cells in stomach tissues, when compared to mice treated with control IgG. Anti-CD40L treatment of the Nlrc5KO mice also resulted in significantly decreased levels of Helicobacter colonization in the stomach, whereas TACI treatment was associated with significantly increased T cell:B cell ratios in both spleens and mesenteric lymph nodes. Furthermore, significantly decreased gastric Il17 expression was found in the anti-CD40L treatment groups, while Ifng expression (indicative of a Th1 response) was significantly lower in TACI treatment groups.

These results identify CD40L and TACI as potential targets for the development of novel therapeutic approaches in human gMALT lymphoma associated with chronic H. pylori infection.