Regulatory T cells : molecular and clinical aspects

Field: Immunology and Microbiology (Life Sciences)

In the immune system’s tug of war with cancer, tolerance mechanisms by which the tumor can \ncontrol anti-tumor immune responses play a central role in determining the outcome. \nRegulatory T cells (Treg) induced in the thymus or the periphery, represent one such tolerance \nmechanism that potentially can be exploited by developing tumors. In this thesis, we explore \nthe underlying molecular mechanisms that result in Treg development, and attempt to elucidate \nthe importance of this T lymphocyte subset in urinary bladder cancer. \n \n \n \nIn humans and mice, the transcription factor FOXP3 is crucial for the function of the Treg \nsubset and maintenance of peripheral tolerance, as illustrated by the lack of functional Treg and \nautoimmune disorders that result from mutations within this protein. In humans however, \nclinical studies of this important T lymphocyte subset are obscured by the fact that FOXP3 is \ntransiently induced in conventional T lymphocytes upon activation. Initially, we address the \nepigenetic regulation of FOXP3 expression, and demonstrate that the committed Treg \npopulation has an almost completely demethylated FOXP3 promoter region, whereas \nconventional non-regulatory CD4+ T lymphocytes are semi-methylated in this region. \nFurthermore, we study the development of regulatory T cells in mice, and assess the \ncontribution and the impact of adenosine receptor signaling on the T lymphocyte compartment. \n \n \n \nNext, the role of the Treg population in urinary bladder cancer is evaluated. First, we investigate \nthe impact of tumor infiltrating CD3+ as well as FOXP3+ T lymphocytes on patient survival. \nSomewhat surprisingly, we find a positive correlation between both CD3+ and FOXP3+ \nlymphocytic infiltrates, suggesting that FOXP3+ lymphocytes in this case may not represent a \ntumor escape mechanism as initially hypothesized. In addition, we observe FOXP3 expression \nin a subset of tumors, and find that this expression is a negative prognostic factor for survival. \nTo follow up these results, we characterize the T lymphocyte immune response in peripheral \nblood, lymph nodes and tumor tissue from patients with UBC. We demonstrate that the \nFOXP3+ fraction of CD4+ T lymphocytes is significantly increased compared to all other \nlocations investigated including macroscopically healthy bladder tissue. Furthermore, these \ntumor infiltrating lymphocytes express high levels of activation and effector markers, but do \nnot display a demethylated pattern in the FOXP3 promoter to match its prominent expression. \nInterestingly, muscle invasive tumors have a lower FOXP3+ fraction at the invasive front \ncompared to non-invasive counterparts. In addition, we observe changes in the cellular immune \nresponse dependent on if the patients have received neo-adjuvant chemotherapy or not, both \nwith regard to cell composition and functional reactivity to tumor antigens. \n \n \n \nEpigenetic regulation governs the commitment of T lymphocytes to the Treg lineage. The fact \nthat FOXP3 expressing tumor infiltrating lymphocytes in UBC do not display a committed \nTreg phenotype could potentially explain the differences in reported clinical impact of this \npopulation in different cancers and has implications for future immunotherapy.