Regulatory T cells : molecular and clinical aspects

In the immune system’s tug of war with cancer, tolerance mechanisms by which the tumor can&#13;\ncontrol anti-tumor immune responses play a central role in determining the outcome.&#13;\nRegulatory T cells (Treg) induced in the thymus or the periphery, represent one such tolerance&#13;\nmechanism that potentially can be exploited by developing tumors. In this thesis, we explore&#13;\nthe underlying molecular mechanisms that result in Treg development, and attempt to elucidate&#13;\nthe importance of this T lymphocyte subset in urinary bladder cancer.&#13;\n&#13;\n&#13;\n&#13;\nIn humans and mice, the transcription factor FOXP3 is crucial for the function of the Treg&#13;\nsubset and maintenance of peripheral tolerance, as illustrated by the lack of functional Treg and&#13;\nautoimmune disorders that result from mutations within this protein. In humans however,&#13;\nclinical studies of this important T lymphocyte subset are obscured by the fact that FOXP3 is&#13;\ntransiently induced in conventional T lymphocytes upon activation. Initially, we address the&#13;\nepigenetic regulation of FOXP3 expression, and demonstrate that the committed Treg&#13;\npopulation has an almost completely demethylated FOXP3 promoter region, whereas&#13;\nconventional non-regulatory CD4+ T lymphocytes are semi-methylated in this region.&#13;\nFurthermore, we study the development of regulatory T cells in mice, and assess the&#13;\ncontribution and the impact of adenosine receptor signaling on the T lymphocyte compartment.&#13;\n&#13;\n&#13;\n&#13;\nNext, the role of the Treg population in urinary bladder cancer is evaluated. First, we investigate&#13;\nthe impact of tumor infiltrating CD3+ as well as FOXP3+ T lymphocytes on patient survival.&#13;\nSomewhat surprisingly, we find a positive correlation between both CD3+ and FOXP3+&#13;\nlymphocytic infiltrates, suggesting that FOXP3+ lymphocytes in this case may not represent a&#13;\ntumor escape mechanism as initially hypothesized. In addition, we observe FOXP3 expression&#13;\nin a subset of tumors, and find that this expression is a negative prognostic factor for survival.&#13;\nTo follow up these results, we characterize the T lymphocyte immune response in peripheral&#13;\nblood, lymph nodes and tumor tissue from patients with UBC. We demonstrate that the&#13;\nFOXP3+ fraction of CD4+ T lymphocytes is significantly increased compared to all other&#13;\nlocations investigated including macroscopically healthy bladder tissue. Furthermore, these&#13;\ntumor infiltrating lymphocytes express high levels of activation and effector markers, but do&#13;\nnot display a demethylated pattern in the FOXP3 promoter to match its prominent expression.&#13;\nInterestingly, muscle invasive tumors have a lower FOXP3+ fraction at the invasive front&#13;\ncompared to non-invasive counterparts. In addition, we observe changes in the cellular immune&#13;\nresponse dependent on if the patients have received neo-adjuvant chemotherapy or not, both&#13;\nwith regard to cell composition and functional reactivity to tumor antigens.&#13;\n&#13;\n&#13;\n&#13;\nEpigenetic regulation governs the commitment of T lymphocytes to the Treg lineage. The fact&#13;\nthat FOXP3 expressing tumor infiltrating lymphocytes in UBC do not display a committed&#13;\nTreg phenotype could potentially explain the differences in reported clinical impact of this&#13;\npopulation in different cancers and has implications for future immunotherapy.

Topic: Immune Cell Function and Interaction
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences