| dc.description.abstract | Classical Hodgkin Lymphoma (CHL) is a germinal centre B cell lymphoma characterised by rare
lymphoma cells within a diverse inflammatory infiltrate. It is unusual amongst haematological
malignancies in that it responds well to PD1 checkpoint blockade. However, evidence for T cell
exhaustion is limited which is surprising given that PD1 checkpoint inhibitors are thought to act
via the reversal of exhaustion. This thesis examines the mechanisms by which CHL cells recruit
and induce a tolerant myeloid and T cell environment, focussing on the role of the PD1-PDL1
axis and the implications of this for the action of checkpoint inhibitors.
The recruitment and induction of a PDL1 positive macrophage phenotype is modelled in vitro
and in primary patient samples, confirming the induction of PDL1 by CHL cells. However, no
phenotypic or functional evidence of T cell exhaustion is detected above that seen in reactive
tissues and no relationship is seen between markers of exhaustion and markers that predict
PD1 inhibitor response challenging the current narrative that PD1 inhibitors in CHL work via
the reversal of exhaustion. Instead, spatial and in vitro modelling identify T helper
differentiation as a putative mechanism for PD1 inhibitor action. They highlight CHL major
histocompatibility complex II expression as playing a central role in the induction of a TH1
regulatory cell rich environment but also as a vulnerability for CHL cells once treatment is
initiated.
As part of this thesis we focus upon multi-parameter imaging analysis. Multi-parameter
imaging enables deep phenotyping whilst retaining spatial relationships between cells.
However, whilst advances in phenotyping approaches have been made there remains a need
for better tools for spatial analysis. We describe the novel application of spatial point pattern
modelling to this task and demonstrate the utility and flexibility of this method in
deconstructing spatial relationships and interactions. | en_US |
