Characterisation of T cell defects in acute myeloid leukaemia

Abstract

Understanding the immune system in patients with cancer and how it interacts with malignant cells is critical for the development of successful immunotherapeutic strategies at a time when novel cancer treatment approaches are required. Acute myeloid leukaemia (AML) results in widespread interaction between the malignant cells and T cells and as such, offers an opportunity to study these interactions. A flow cytometric analysis of T cells in the peripheral blood of patients presenting with AML illustrated that the absolute number of T cells is increased in AML compared with healthy controls. Furthermore, a large population of CD3+56+ cells was identified. These cells are not natural killer T cells but effector T cells that may represent a failing immunosurveillance mechanism. Two technical issues were explored: how to separate T cells from the peripheral blood of newly diagnosed AML patients and the impact of the method of immunomagnetic cell separation on the gene expression profile of healthy T cells. Gene expression profiling was subsequently performed on T cells from AML patients compared with healthy controls. Global differences in transcription were observed suggesting aberrant T cell activation patterns in AML. As differentially regulated genes involved in actin cytoskeletal formation were noted, a functional assessment of the ability of T cells from AML patients to form immunological synapses was performed. This illustrated that although T cells from AML patients can form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signalling molecules to that signalling interface is impaired. Taken together, these findings demonstrate that numerically T cells are plentiful in AML however they are abnormal in terms of the genes they are transcribing and in their interactions with tumour cells. Targeting immunological synapse formation may represent an important means of improving T cell recognition of tumour cells across a range of cancers.