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The role of TNFR2+ regulatory T cells in human cancers
thesisposted on 27.02.2017, 22:14 by Govindaraj, Chindu
Cancer is currently the leading cause of death worldwide. Almost all human cancers present with high numbers of regulatory T cells (Tregs) within their tumor microenvironment. Regulatory T cells are a subset of T cells that have detrimental effects within cancer patients as they can dampen anti-tumor immunity and enable cancer progression. Additionally, most cancer patients have high levels of the pro-inflammatory cytokine, tumor necrosis factor (TNF), which can induce TNF Receptor 2 (TNFR2) on Tregs. TNFR2+ Tregs represent a highly potent Treg subset, and depletion of these cells results in tumor eradication within murine mesothelioma models. As there are currently no studies on TNFR2+ Tregs in human cancers, this PhD aimed to investigate the role of TNFR2+ Tregs in ovarian cancer and in acute myeloid leukemia (AML). The results demonstrate that TNFR2+ Tregs are indeed present at elevated levels within the tumor microenvironment (ascites) of newly diagnosed ovarian cancer patients, and within the peripheral blood as well as the tumor microenvironment (bone marrow) of newly diagnosed AML patients. Additionally, these cells were also present at elevated levels within the peripheral blood of AML patients at clinical remission, suggesting that they are resistant to current standard induction chemotherapy. Elevated levels within the tumor microenvironment were partly attributed to the selective migration of TNFR2+ Tregs from the peripheral blood into the tumor microenvironment, for both ovarian cancer as well as AML patients. These Tregs were significantly more suppressive in function within ascites when compared to those from the peripheral blood of ovarian cancer patients, while they had a similar functional phenotype when comparing the peripheral blood and the bone marrow of newly diagnosed AML patients. The novel combined therapy of the chemotherapeutic drugs, panobinostat and azacitidine, when administered to newly diagnosed AML patients as an induction therapy, was able to selectively reduce TNFR2+ Treg proportions within the peripheral blood of all patients. This reduction was, however, observed within the bone marrow of only a proportion of the patients who did clinically better, demonstrating that TNFR2+ Treg proportions within the bone marrow of newly diagnosed AML patients are correlated with disease outcome. In vitro studies suggested that panobinostat may be responsible for the observed reduction of TNFR2+ Tregs. Furthermore, administration of the chemotherapeutic drug lenalidomide, a TNF inhibitor, along with azacitidine to AML patients at clinical remission as a maintenance therapy, was also able to reduce TNFR2 levels on CD4 T cells, as well as TNFR2+ Treg levels within the peripheral blood of a proportion of the patients who did clinically better. In vitro studies suggested that lenalidomide may be responsible for the reduction of TNFR2 levels, however this was not via its ability to inhibit TNF production, indicating a novel mechanism. Collectively, the results demonstrate that TNFR2+ Tregs are present at elevated levels within human ovarian cancer and AML patients and that a number of chemotherapeutic drugs can selectively reduce the proportion of TNFR2+ Tregs, with this reduction being correlated with a better clinical outcome. Targeting TNFR2+ Tregs therefore appears to be a promising strategy to further improve the current poor prognosis of cancer patients.