Investigating the role of tumour-associated macrophages in a mouse model of B-cell Non- Hodgkin Lymphoma

Abstract

A large number of infiltrating tumour-associated macrophages (TAM) is associated with a poor prognosis in many diverse cancers. In B-cell Non- Hodgkin Lymphomas (B-NHL), the situation is less clear with conflicting reports on the clinical significance of the total number of macrophages. Comprehensive gene expression analysis of unsorted diagnostic biopsy specimens in the two most common B-NHL, Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL), implies differential expression of macrophage genes between good and bad prognosis cases. The hypothesis being tested in this thesis is that macrophages play a fundamental role in the progression of BNHL. This functional significance may not be fully reflected simply by counting the numbers of macrophages, but rather by revealing the functional roles of TAM in lymphoma. In this thesis we critically review the clinical and laboratory evidence relating to lymphoma-macrophage interactions, before detailing our own laboratory investigations. The laboratory goal of this project is to establish proof-ofconcept, principally using mouse models, that TAM are partners in a lymphomasupporting microenvironment. A large number of diagnostic human biopsies of DLBCL were interrogated for evidence of correlations between macrophage numbers, phenotype, and tumour proliferation. Our subsequent experimental strategy was to manipulate the numbers and phenotype of TAM in a transgenic Myc-driven mature B-lymphoma transplanted to immune-competent hosts. The use of macrophage ablation with toxic liposomes, and with a transgenic host possessing drug-inducible macrophage-specific cell death, explored the impact of gross macrophage depletion in lymphoma. Adoptive transfer experiments investigated the impact of supplementary macrophages of different phenotypes. The administration of a colony-stimulating factor-1 receptor (CSF-1R) inhibitor was used to block the accumulation of TAM in growing lymphoma, and act as a pre-clinical model for this promising class of therapeutic agents. We detail the first reported use of CSF-1R inhibition in a model of B-NHL, and discuss the efficacy and consequences of this strategy. CSF-1R inhibition reduces circulating monocyte and TAM numbers and diminishes lymphoma growth.