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Title: Identifying and targeting defective immune surveillance mechanisms in myeloma using multi-parameter single cell profiling by mass cytometry
Author: Seymour, Frances Louise
ISNI:       0000 0004 9355 6832
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2020
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Myeloma is a complex, incurable bone marrow malignancy of plasma cells with a diverse clinical course. Existing data suggests that abnormalities in T cell function and PD1 expression are present in myeloma and that immune subversion may be playing a role in progression of the disease. I hypothesise that characterisation of the cellular immunological landscape in myeloma will identify distinct functional populations which may offer therapeutic targets to restore immunological control of the disease. Mass cytometry is a novel, single cell analysis technique which enables simultaneous assessment of more than 30 cell surface and intracellular antigens by utilising metal tagged antibody probes. Using this technology and an algorithmic based data analysis approach alongside traditional data analysis techniques I explored the bone marrow microenvironment in 9 control, 18 NDMM and 9 RRMM samples. RRMM samples were drawn from patients receiving dual targeting of CD38 and PDL1. In NDMM I demonstrate that immune microenvironment changes include defects in antigen presenting populations, effector and helper lymphocyte populations and NK cells. These changes are present before treatment has been initiated and have prognostic significance. These functional defects are associated with upregulation of PD1 and PDL1 expression across multiple lineages. In the RRMM setting treatment targeting PDL1 and CD38 results in early functional cytotoxicity and cytokine production signals. Defective immunological responses correlate with poor clinical outcome and there is potential to restore immune function, providing a strong argument for considering multi-lineage immunological damage to represent a form of symptomatic myeloma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available