| dc.description.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. | en_US |
