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Title: Dissecting the inflammatory response in melanoma
Author: Barker, Laura Jane
ISNI:       0000 0004 6497 3741
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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While the immune system can control tumour growth, regulatory mechanisms, necessary in preventing immunopathology & autoimmunity, contribute to tumour progression impeding elimination of immunogenic tumours such as melanoma. To identify how the inflammatory response can influence tumour biology & be targeted in immunotherapy it is necessary to understand how expression of inflammatory molecules involved in regulatory mechanisms is controlled, which aspects of the inflammatory response are associated with accumulation of immune-regulatory populations & how these impact on frequency & activity of cells involved in tumour control. Tumour-associated macrophages & regulatory T cells possess key tumour-promoting functions, including production of the suppressive cytokine, interleukin 10 (IL-10). I have analysed IL-10 regulation in myeloid cells by disrupting a putative enhancer. The tumour inflammatory environment can influence neutrophil biology, leading to accumulation of low-density granulocytes, suggested to have immunosuppressive functions. I investigated the nature & frequency of low-density granulocytes in melanoma & their correlation with the inflammatory response & disease outcome. I identified low-density cells with an activated phenotype & cells with an immature phenotype enriched in the peripheral blood of stage IV melanoma patients. Marked inter-patient variation in the frequency of these subsets that correlated with accumulation of distinct cytokines, suggested the existence of distinct inflammatory axes. Analysis of patients undergoing anti-CTLA-4 treatment revealed that a lower frequency of activated neutrophils before treatment & an increase in frequency during treatment were associated with better response to anti-CTLA-4. To establish whether accumulation of distinct neutrophil subsets was linked to wider inflammatory changes, the frequency of other immune cell subsets was determined. An enrichment of immature neutrophils was associated with TH2 cell enrichment, whereas an enrichment of activated neutrophils associated with inflammatory monocytes & activated TCR-?d T cells, further supporting the existence of distinct inflammatory axes. The frequency of activated neutrophils negatively correlated with CCR4+ CXCR3+ CD8+ effector memory T cells, perhaps reflecting greater tumour infiltration of this population. Given the association of this subset with a neutrophil population linked to anti-CTLA-4 response, the importance of CD8+ T cells in anti-tumour responses, & the fact this population had not previously been described, I attempted further characterisation, as well as characterisation of intratumoural CD8+ T cells.
Supervisor: Cerundolo, Vincenzo ; Middleton, Mark Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available