Anti-CD40L therapy prevents the formation of precursor lesions to gastric B-cell MALT lymphoma in a mouse model

Le Ying, Phoebe Liu, Zhoujie Ding, Georgie Wray-McCann, Jack Emery, Nina Colon, Lena H.M. Le, Le Son Tran, Ping Xu, Liang Yu, Dana J. Philpott, Yugang Tu, Daryl M.Z. Cheah, Chee L. Cheng, Soon T. Lim, Choon K. Ong, Richard L. Ferrero

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Abstract

Mucosa-associated lymphoid tissue (MALT) lymphoma is a B-cell tumour that develops over many decades in the stomachs of individuals with chronic Helicobacter pylori infection. We developed a new mouse model of human gastric MALT lymphoma in which mice with a myeloid-specific deletion of the innate immune molecule, Nlrc5, develop precursor B-cell lesions to MALT lymphoma at only 3 months post-Helicobacter infection versus 9–24 months in existing models. The gastric B-cell lesions in the Nlrc5 knockout mice had the histopathological features of the human disease, notably lymphoepithelial-like lesions, centrocyte-like cells, and were infiltrated by dendritic cells (DCs), macrophages, and T-cells (CD4+, CD8+ and Foxp3+). Mouse and human gastric tissues contained immune cells expressing immune checkpoint receptor programmed death 1 (PD-1) and its ligand PD-L1, indicating an immunosuppressive tissue microenvironment. We next determined whether CD40L, overexpressed in a range of B-cell malignancies, may be a potential drug target for the treatment of gastric MALT lymphoma. Importantly, we showed that the administration of anti-CD40L antibody either coincident with or after establishment of Helicobacter infection prevented gastric B-cell lesions in mice, when compared with the control antibody treatment. Mice administered the CD40L antibody also had significantly reduced numbers of gastric DCs, CD8+ and Foxp3+ T-cells, as well as decreased gastric expression of B-cell lymphoma genes. These findings validate the potential of CD40L as a therapeutic target in the treatment of human gastric B-cell MALT lymphoma.

Original languageEnglish
Pages (from-to)402-414
Number of pages13
JournalJournal of Pathology
Volume259
Issue number4
DOIs
Publication statusPublished - Apr 2023

Keywords

  • APRIL
  • B-cell
  • BAFF
  • CD40 ligand
  • Helicobacter
  • MALT lymphoma
  • multiplex immunohistochemistry
  • NLRC5
  • PD-L1

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