Marzolini, Maria Ann Veronica; (2019) The characterisation and manipulation of a novel subset of tumour-reactive CD4+ cytotoxic T lymphocytes in human cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The ability of cytotoxic CD4+ T lymphocytes (CD4+ CTLs) to exert anti-tumour effects has been demonstrated in murine models of melanoma and an increase in the number of CD4+CTLs has previously been identified in the peripheral blood of patients with Chronic Lymphocytic Leukaemia (CLL) as well as in Hepatocellular Carcinoma. The project’s objective was to further characterise CD4+ CTLs in human cancer and in particular in haematological malignancies. CD4+ CTLs were identified in the peripheral blood, lymph nodes and bone marrow trephine biopsies of patients with CLL. There was a significant increase in the percentage of CD4+ CTLs in the blood of Cytomegalovirus (CMV) seropositive patients with CLL. The immunophenotype of the cells was similar to CD8+ CTLs with respect to the expression of EOMES, CD57 and loss of CD27 and CD28. CD4+ CTLs were also identified in other haematological malignancies, including in the bone marrow aspirates of patients with Multiple Myeloma and in the lymph node biopsies of patients with Non-Hodgkin and Hodgkin Lymphoma. We were able to isolate CD4+ CTLs, rapidly expand them and show that they have the ability to secrete Interferon gamma as well as Granzyme B. We also performed an extensive phenotyping of the cells with CyTOF (mass cytometry) technology. Further study is required to examine the molecular and cellular determinants of their cytotoxic activity prior to exploring the potential to manipulate them for therapeutic benefit.

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