Characterisation of the mechanisms of tumour-induced dysfunction of clonal T cell expansions in multiple myeloma

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Multiple myeloma is a cancer involving malignant plasma cells in the bone marrow. Despite advances in therapy, relapse is inevitable due to residual disease and myeloma remains incurable. New therapies are required to remove residual disease and maintain long term survival. Expanded clones of cytotoxic T cells have been detected in myeloma and their presence is associated with improved survival, suggesting a role in anti-tumour immunity. However, these cells are dysfunctional as they do not proliferate. Thus, tumour-induced dysfunction of T cell clones may be a tumour evasion mechanism that contributes to immune escape. The primary aim of this thesis was to elucidate the mechanism/s responsible for the observed dysfunction of these T cell clones, which may allow future development and implementation of novel strategies to restore clonal T cell function. T cell clones were detected in 75% of a new cohort of myeloma patients (n=103) and their presence was associated with an improved survival, despite being non-proliferative. T cell clones were present in 100% of long term survivors of myeloma, providing further evidence that these cells prolong survival. In contrast, T cell clones from 10 year survivors were proliferative. Phospho-flow technology was used to investigate the differences in cell signalling pathways between T cell clones of 10 year and non-10 year survivors. The dysfunction in these cells was related to the upregulation of the SMAD pathway, promoting T cell inactivation and downregulation of the ERK pathway, which blocks proliferation of T cells. Classification of T cell clones into an anergic, exhausted or senescence phenotype was carried out to determine if dysfunction is reversible, since reversal of dysfunction is phenotype dependent. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28- with normal telomere lengths for age, suggesting telomere-independent senescence. Importantly, the results demonstrate that dysfunction is potentially reversible. The p38-MAPK, p16 and p21 signaling pathways, which are known to induce senescence were not upregulated. However, elevated telomerase levels may explain how senescent T cells maintain normal telomere lengths. This thesis expands our understanding of the biology and clinical significance of T cell clones. It is the first to describe the dysfunction of T cell clones as telomere independent senescence, which is potentially reversible. Additionally, it has identified two novel mechanisms by which tumour cells induce dysfunction in T cell clones. These findings have implications for reversing tumour-induced dysfunction of T cell clones in patients with myeloma.
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