Investigation of the influence of CD4+CD25+ regulatory cells on the generation of tumour immunity in mice and human patients.

Abstract

A population of T cells identified as CD4+CD25+FOXP3+ (Tregs) are present in rodents and humans. These cells are vital for suppressing the activity of conventional self- reactive T cells. Previous work conducted using tumour cell lines has indicated that Tregs also suppress effective anti-tumour immunity in mice. Existing data derived using immunocompromised strains of mice has strongly suggested that the immune system is capable of recognising malignant cells, a process termed immunosurveillance. It was reasonable to hypothesise therefore that Tregs impinge on this process, effectively hampering elimination of tumour cells by the immune system. This hypothesis was tested in this thesis by analysing the impact of Tregs on tumours induced in vivo using the chemical carcinogen, methylcholanthrene. Results of these studies indicated that chemically induced tumours are significantly infiltrated with Tregs and that partial depletion of theses cells prior to exposure to the carcinogen results in a marked reduction in tumour incidence. These findings support a role for Tregs in immunosurveillance. The role of Tregs during human malignancy was also addressed in this thesis using blood samples obtained from a cohort of patients with colorectal cancer. Specifically, studies were carried out to determine whether Treg frequencies were elevated in this group compared to healthy controls and to address whether these cells suppressed tumour antigen specific T cell responses. Results of these studies indicated that that colorectal carcinoma patients have an elevated frequency of Tregs in peripheral blood compared to age matched controls and that these Tregs suppress CD4+ T cell responses to tumour antigens. Collectively these data indicate that Tregs downmodulate immune responses to tumours and support strategies aimed at depleting or inactivating the cells for therapeutic purposes