Characterisation of Positive and Negative Influences in Tumour Immunity

The main function of our white cells is to eliminate infectious agents such as bacteria and viruses. These cells form part of the immune system and their activation is known as an immune response. Certain types of white cells, known as regulatory T cells, are believed to dampen down immune responses that are considered harmful ?these may be immune responses directed towards normal, uninfected tissues. Since tumours arise from normal tissues, it was considered possible that these regulatory T cells inhibit immune responses to tumours. Several laboratories have shown that the cells do indeed inhibit immune responses to tumours, responses that could otherwise promote tumour destruction.
A two-pronged approach is now warranted to find out how this information can be harnessed for the purposes of treating people with cancer. Firstly, the immune responses capable of promoting tumour destruction must be identified and secondly the precise way in which regulatory T cells act to stop these responses working effectively must be discovered. This approach will allow us to determine how the immune system can be manipulated for the treatment of a wide variety of cancers, including breast cancer, lung cancer, ovarian cancer and colorectal cancer.

Many fundamental questions remain unanswered in the field of tumour immunology. The type of immune effector cells / molecules capable of controlling tumour growth in vivo have not yet been definitively identified. In addition, whilst many pathways of tumour-induced immunosuppression are thought to contribute to the overall paucity of anti-tumour immunity, these pathways remain poorly characterised. A resurgence of interest in T cell mediated tolerance has revealed that a subpopulation of T cells, named regulatory T cells (Tregs) may play a key role in inhibiting effective anti-tumour immunity. These Tregs, identified by expression of the CD4 antigen and the forkhead transcription factor, Foxp3, keep innate and adaptive immune responses in check; suppress responses to self- and non-self antigens and impinge on almost all aspects of immune activity including transplantation, allergy, infection, autoimmunity and tumour immunity. A clear objective of Treg research is to determine how they can be manipulated therapeutically to treat a wide range of immune-based diseases.
Cancer is a disease where manipulation of Treg activity has obvious therapeutic potential. An enormous body of work indicates that overall, Tregs are present at an increased frequency in the peripheral blood lymphocytes (PBL) of patients with cancer compared to healthy controls. Depletion of Tregs from PBL in vitro, uncovers T cell responses to tumour antigens and, in vivo, depletion of Tregs can enhance immune responses generated following vaccination. Furthermore, several reports indicate that high frequencies of Tregs correlate with more advanced disease implying that Tregs facilitate progression of cancer. I hypothesize that tumour development can be prevented or controlled at an early stage by effective immune responses. However, these responses are suppressed by Tregs. The identification of immune mechanisms of tumour control and an understanding of how Tregs impinge on these will enable therapeutic strategies to be developed for the successful treatment of patients with cancer. Detailed investigations into both issues will be undertaken. Specifically, the study aims to identify the effector cells/molecules that participate in controlling tumour growth in vivo and to assess the consequences of this immune activity on the fate of the tumour. In addition, an investigation of Treg activity in tumours will be performed. The overall aim of this two-pronged approach, which involves evaluating both positive and negative influences on tumour immunity, is to inform the design of more effective therapeutic immune interventions for patients with cancer.