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

• Published in: The Journal of pathology Vol. 259; no. 4; pp. 402 - 414
• Main Authors: Ying, Le, Liu, Phoebe, Ding, Zhoujie, Wray‐McCann, Georgie, Emery, Jack, Colon, Nina, Le, Lena HM, Tran, Le Son, Xu, Ping, Yu, Liang, Philpott, Dana J, Tu, Yugang, Cheah, Daryl MZ, Cheng, Chee L, Lim, Soon T, Ong, Choon K, Ferrero, Richard L
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.04.2023; Wiley Subscription Services, Inc
• Subjects: Animal models; Animals; Antibodies; Apoptosis; APRIL; B-Lymphocytes; BAFF; B‐cell; CD4 antigen; CD40 Ligand; CD40L protein; CD8 antigen; Cell culture; Chronic infection; Dendritic cells; Forkhead Transcription Factors - metabolism; Foxp3 protein; Helicobacter; Helicobacter Infections - complications; Helicobacter Infections - drug therapy; Helicobacter pylori - genetics; Immune checkpoint; Infections; Intracellular Signaling Peptides and Proteins - metabolism; Lesions; Lymphoid tissue; Lymphoma; Lymphoma, B-Cell, Marginal Zone - drug therapy; Lymphoma, B-Cell, Marginal Zone - genetics; Lymphoma, B-Cell, Marginal Zone - prevention & control; Macrophages; Malignancy; MALT lymphoma; Medicin och hälsovetenskap; Mice; Microenvironments; Mucosal-associated lymphoid tissue; multiplex immunohistochemistry; NLRC5; Original; PD-L1 protein; PD‐L1; Stomach Neoplasms - pathology; Therapeutic targets; Tumor Microenvironment; Tumors; BAFF; multiplex immunohistochemistry; MALT lymphoma; B-cell; Helicobacter; CD40 ligand; NLRC5; PD-L1; APRIL
• DOI: 10.1002/path.6053
• ISSN: 0022-3417; 1096-9896

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. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.