An investigation of the role of complement in acute myeloid leukaemia

Kempshall, Emma 2016. An investigation of the role of complement in acute myeloid leukaemia. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Acute myeloid leukaemia (AML) affects about 3000 people in the UK each year. Chemotherapy leads to complete remission in most patients but, up to 70% relapse. The success of allogeneic stem cell transplant (SCT) demonstrates that donor T cells can eliminate residual tumour through a graft-versus-leukaemia effect however, SCT is only viable in a minority of patients. Responses seen with alternative approaches, such as adoptive immunotherapy with tumour specific T cells or inducing T cells by vaccination, have been disappointing, highlighting a clear need for new immunotherapeutic approaches. Immune responses against leukaemia are inhibited by a range of suppressive mechanisms. Identification of novel therapeutic targets capable of unleashing natural and effective immune responses is critical. The complement system is an enzyme cascade with diverse effector functions instituted by both the innate and adaptive immune systems. Recent evidence suggests that complement promotes the progression of malignancy. The role of complement in AML is largely unexplored but the limited data available implies that complement could have a critical role in both the initiation and progression of AML. Sub-lytic complement protects cells against further attack by both lytic doses of complement and other pore-formers including perforin, the cytolytic protein used by both NK and CD8+ T cells. This phenomenon termed complement-induced protection (CIP). Thus cancer cells exposed to sub-lytic complement may be protected from lysis by NK and CD8+ T cells with significant consequences for immune escape. When this hypothesis was tested using an in vitro model of NK cell killing, no evidence of protection against NK cell killing was observed despite clear CIP against further complement attack. Despite a strongly protective phenotype, subsequent microarray analysis revealed no genetic signature for CIP indicating that mechanisms underpinning CIP require no changes in gene expression. A mouse model was then used to test the hypothesis that complement promotes progression of AML. The use of both genetically modified mice lacking various complement components and complement inhibitors in wild-type animals, revealed that complement promotes AML progression. CIP was a potential mechanism by which tumours might escape immune elimination in vivo, however, this was only a small component of the almost complete protection observed in C3 deficient mice. Putative mechanisms include inhibition of CD8+ T cells and promoting AML seeding. Should complement prove to have a key role in human AML, available complement therapeutics could progress rapidly into human studies. These might not only have an independent role in improving spontaneous immune responses, but might also impact on all available or novel immune mediated therapies for AML.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit:	3 January 2017
Last Modified:	17 Jan 2022 12:03
URI:	https://orca.cardiff.ac.uk/id/eprint/97030

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