Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.823587
Title: Dissecting the immune environment in glioblastoma
Author: Ma, Ruichong
ISNI:       0000 0005 0291 994X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Abstract:
Glioblastoma (GBM) is the most common primary brain tumour in adults. Unfortunately, it is also the most malignant, conferring a median survival of only 6 months, increasing to 14-24 months with maximal therapy. Despite much effort, there have been relatively little effective advances made for the treatment of GBM in the last decade. Immunotherapy, especially checkpoint inhibition, has revolutionised the management of some previously untreatable cancers, such as metastatic melanoma. However, such treatments have yet to be shown to have any significant effect for the treatment of GBM. This is in part due to the low tumour mutational burden and poor immunogenicity of this immune 'cold' tumour. In this thesis I show that there are potential neoantigen encoding mutations, as well as a wide range of cancer testis antigens, that are not expressed or minimally expressed in GBM. Treatment of U87MG and GBM primary cell lines with the DNA methlytransferase inhibitor decitabine, leads to an increase in the expression of these immunogenic antigens due to hypomethylation. This increase in antigen expression leads to increased T cell recognition, activation and killing in a major histocompatibility complex - T cell receptor (TCR) dependent fashion. Further experiments are planned to translate these in vitro findings into an in vivo mouse model with a view to establishing a clinical trial. Secondly, I also present single cell TCR sequencing data performed on primary and recurrent GBM samples from 13 patients. I show that the TCR diversity is much reduced in the tumour samples with many more expanded T cell clones. I further show that testing of the expanded TCR reveals some of these T cell clones are tumour reactive, but they are not the most significantly expanded clones. Further work is being undertaken to further characterise the tumour specific TCR identified in more detail as well as interrogate the clonal TCR seen in other patients.
Supervisor: Cerundolo, Vincenzo Sponsor: CRUK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.823587  DOI: Not available
Keywords: Cancer ; Supratentorial brain tumors ; Immunology
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