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1	A NOVEL APPROACH TO SELECTIVELY TARGET AND REPROGRAM REGULATORY T CELLS IN THE TUMOR MICROENVIRONMENT Rami Akram Alfar (13949481) 13 October 2022 (has links) <p> Although immune checkpoint inhibitors block one mechanism of regulatory T cell (Treg) immunosuppression, no drug has been designed to inhibit all immunosuppressive activities of Tregs. We describe here a mechanism for manipulating Treg function in a tumor microenvironment without altering their properties in healthy tissues. For this purpose, we first identify a small molecule that binds specifically to Tregs in tumors but not in healthy tissues. We then exploit this binder to deliver an attached imaging agent or an immune activator specifically into tumor-resident Tregs. Analysis of the resulting tumors demonstrates that targeting of a Toll-like receptor 7 agonist to tumor Tregs inhibits their expression of FOXP3, PD-1, CTLA4, and HELIOS, resulting in 40-80% reduction in tumor growth and repolarization of other tumor-infiltrating immune cells to more inflammatory phenotypes. Since Tregs comprise <1% of cells in the tumor masses examined, these data argue that Tregs exert a disproportionately large effect on tumor immunity. The data also demonstrate that the immunosuppressive properties of Tregs can be manipulated without altering their properties in healthy tissues.</p> Regulatory T cells Folate receptor delta Tumor immunosuppression
2	Aberrations in Cytokine Signaling in Leukemia: Variations in Phosphorylation and O-GlcNAcylation Tomic, Jelena 31 August 2012 (has links) Tumor-induced immunosuppression can occur by multiple mechanisms, each posing a significant obstacle to immunotherapy. Evidence presented in this dissertation suggests that aberrant cytokine signaling, as a result of altered metabolism of Chronic Lymphocytic Leukemia (CLL) cells, confers a selective advantage for tumor survival and growth. Cells from CLL patients with aggressive disease (as indicated by high-risk cytogenetics) were found to exhibit prolongation in Interferon (IFN)-induced STAT3 phosphorylation, and increased levels of reactive oxygen species (ROS) in these cells reflected these signaling processes. Changes in the relative balance of phospho-STAT3 and phospho-STAT1 levels, in response to combinations of IL-2 + Toll-like receptor (TLR)-7 agonist + phorbol esters, as well as IFN, were associated with the immunosuppressive and immunogenic states of CLL cells. In addition, immunosuppressive leukemic cells were found to express high levels of proteins with O-linked N-acetylglucosamine (O-GlcNAc) modifications, due to increased metabolic activity through the Hexosamine Biosynthetic Pathway (HBP), which caused impaired intracellular signaling responses and affected disease progression. A conclusion of the studies presented here is that the intrinsic immunosuppressive properties of leukemic cells may be overcome by agents such as Resveratrol that target metabolic pathways of these cells. Chronic Lymphocytic Leukemia Immunogenicity Interferon (IFN) STAT3 Reactive Oxygen Species (ROS) Tumor suppressor p53 phosphatases Toll-like receptor (TLR)-7 agonist phorbol esters immunosuppressive cytokines O-GlcNAc Hexosamine Biosynthetic Pathway (HBP) Glucosamine Resveratrol Friend Erythroleukemia RL2 antibody cancer vaccines IL-2 tumor immunosuppression phosphorylation O-GlcNAcylation cytotoxic T lymphocytes (CTLs) Ataxia telangiectasia mutated (ATM) Antigen presenting cell (APC) Immunotherapy OGT OGase glucose tumor metabolism PKC CD83 Warburg effect tumor microenvironment IL-10 tumor-reactive T cells
3	Aberrations in Cytokine Signaling in Leukemia: Variations in Phosphorylation and O-GlcNAcylation Tomic, Jelena 31 August 2012 (has links) Tumor-induced immunosuppression can occur by multiple mechanisms, each posing a significant obstacle to immunotherapy. Evidence presented in this dissertation suggests that aberrant cytokine signaling, as a result of altered metabolism of Chronic Lymphocytic Leukemia (CLL) cells, confers a selective advantage for tumor survival and growth. Cells from CLL patients with aggressive disease (as indicated by high-risk cytogenetics) were found to exhibit prolongation in Interferon (IFN)-induced STAT3 phosphorylation, and increased levels of reactive oxygen species (ROS) in these cells reflected these signaling processes. Changes in the relative balance of phospho-STAT3 and phospho-STAT1 levels, in response to combinations of IL-2 + Toll-like receptor (TLR)-7 agonist + phorbol esters, as well as IFN, were associated with the immunosuppressive and immunogenic states of CLL cells. In addition, immunosuppressive leukemic cells were found to express high levels of proteins with O-linked N-acetylglucosamine (O-GlcNAc) modifications, due to increased metabolic activity through the Hexosamine Biosynthetic Pathway (HBP), which caused impaired intracellular signaling responses and affected disease progression. A conclusion of the studies presented here is that the intrinsic immunosuppressive properties of leukemic cells may be overcome by agents such as Resveratrol that target metabolic pathways of these cells. Chronic Lymphocytic Leukemia Immunogenicity Interferon (IFN) STAT3 Reactive Oxygen Species (ROS) Tumor suppressor p53 phosphatases Toll-like receptor (TLR)-7 agonist phorbol esters immunosuppressive cytokines O-GlcNAc Hexosamine Biosynthetic Pathway (HBP) Glucosamine Resveratrol Friend Erythroleukemia RL2 antibody cancer vaccines IL-2 tumor immunosuppression phosphorylation O-GlcNAcylation cytotoxic T lymphocytes (CTLs) Ataxia telangiectasia mutated (ATM) Antigen presenting cell (APC) Immunotherapy OGT OGase glucose tumor metabolism PKC CD83 Warburg effect tumor microenvironment IL-10 tumor-reactive T cells

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