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• W3024585412 abstract "Novel, promising strategies to fight cancer include immunotherapeutic approaches these days. Such strategies are regarded as breakthrough of the 21th century. The Nobel Prize of medicine was recently awarded to the discovery of ways to remove the immune system’s “brakes” (checkpoints) and thereby unleashing immune cells to attack tumors. However, only in a limited cohort of patients a persisting tumor regression is achieved. Besides avoiding immune recognition by the expression of such checkpoint molecules or the lack of antigen presentation, the metabolic tumor microenvironment contributes to diminished anti-tumor immune responses. The tumor microenvironment is characterized by low levels of nutrients and at the same time the accumulation of immunosuppressive metabolites as lactic acid, both negatively affecting the anti-tumor immune response. Therefore, targeting tumor metabolism could improve the efficacy of immunotherapeutic approaches. The link between metabolism and T cell effector functions is still a matter of debate and data on the human system are rather sparse particularly for different CD8 T cell subsets. Understanding this link is a prerequisite for the development of therapies targeting tumor cells, but preserving immune cell functions.Thus in this thesis, CD8 T cell subsets (naive, central and effector memory T cells) were characterized in terms of their metabolic demands for different aspects of function as proliferation or cytokine secretion. Nutrient restriction experiments were performed to reveal metabolic dependencies of CD8 T cells and finally the impact of anti-metabolic drugs as proposed for cancer treatment was analyzed.In comparison to murine T cells, human CD8 T cells seem to be less dependent on glucose metabolism, as cell growth and effector functions as cytokine secretion were only slightly compromised under glucose deprived conditions. However, proliferation was blocked in all three subsets. Interestingly, the variation between donors was pretty high especially in naive T cells.In contrast, glutamine was essential for CD8 T cell function as glutamine restriction led to insufficient activation of all CD8 T cell subsets. Nevertheless, effector functions as IFNγ and TNF secretion were less compromised under glutamine deprived conditions in memory subsets than in naive T cells. Titration experiments showed that glutamine concentrations as low as 0.1 mM inhibited T cell activation and IFNγ and TNF secretion, a concentration which has been already detected in tumors. Proliferation was already significantly reduced at a glutamine concentration of 0.25 mM. These results showed that not only glucose but also glutamine is a substrate, tumor cells and immune cells have to compete for in the tumor microenvironment. Experiments failed to find a combination of metabolites downstream of glutamine degrading pathways which can substitute for glutamine, indicating that glutamine itself is crucial for T cells. Preliminary results suggest that the lack of glutamine synthetase, an enzyme catalyzing the reaction of glutamate to glutamine, could play a role in the dependency on glutamine in T cells.Next, the role of cellular respiration was analyzed by application of oligomycin, an ATP synthase inhibitor. T cell functions as proliferation as well as IFNγ and TNF secretion were diminished in naive T cells but only slightly in central and effector memory T cells.Although effector memory T cells are regarded as an exhausted subset, our findings suggest that these cells are less affected by nutrient restriction than naive T cells. Therefore also effector memory T cells should be considered in terms of immunotherapeutic approaches as adoptive T cell transfer.Finally, as activated T cells show an accelerated metabolism similar to tumor cells, the impact of anti-metabolic drugs was investigated in freshly stimulated CD8 T cells. With special regard to adoptive T cell transfer, the impact of clinically relevant anti-metabolic drugs was investigated in expanded CD8 T cells.Due to the importance of glutamine for T cell activation, the application of inhibitors targeting glutamine metabolism has to be considered carefully. Due to this fact the impact of glutamine analogues (DON and acivicin) as well as glutaminase inhibitors (BPTES and CB-839) was analyzed in this study. Inhibition of glutaminase, converting glutamine to glutamate, had no impact on T cell function in primary stimulated CD8 T cells, whereas the glutamine analogs strongly impaired T cell function and metabolic activity. Surprisingly, DON did not show a strong impact on expanded CD8 subsets.Since glucose metabolism is of major importance for tumor cells, the impact of drugs targeting glycolysis on T cells was analyzed. Inhibition of monocarboxylate transporter (MCTs) in tumor cells, to block lactic acid secretion, affects tumor cells itself but might also support the anti-tumor immune response by reducing lactate accumulation. Up to now potent MCT inhibitors have been developed only for MCT1 and MCT2. The two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib, both known cyclooxygenase (COX) inhibitors, target MCT1 and MCT4. As they are the only identified inhibitors of MCT1 and simultaneously MCT4, they might be promising substances in the context of tumor therapy. Although an inhibition of glycolytic activity was observed, cytokine secretion was maintained in human naive and effector memory CD8 T cell subsets and also in expanded CD8 T cell subsets. Only a reduction in proliferation was observed after six days. These results were further supported by investigating a complete MCT1 and MCT4 inhibition in murine T cells. To mimic this pan-MCT inhibition, MCT4 deficient T cells were cultured in the presence of a MCT1/2 inhibitor. Although the glycolytic activity was almost completely blocked, murine T cells were still able to secret important effector cytokines such as IFNγ; however levels were moderately reduced.In this thesis, CD8 T cells showed subset specific differences in their metabolic activity. While glucose restriction did not harmed T cell function, glutamine deprivation had a strong impact on the T cell immune response. Therefore, targeting glucose metabolism is a promising strategy in cancer therapy, while drugs acting on the glutamine metabolism have to be considered carefully. Nevertheless, T cells were unaffected by glutaminase inhibitors. These findings suggest that anti-metabolic drugs are promising supplements in immunotherapeutic approaches as checkpoint blockade or adoptive T cell transfer therapy." @default.
• W3024585412 created "2020-05-21" @default.
• W3024585412 creator A5021285843 @default.
• W3024585412 date "2020-05-08" @default.
• W3024585412 modified "2023-09-27" @default.
• W3024585412 title "Impact of drugs targeting tumor metabolism on CD8 T cell effector function" @default.
• W3024585412 hasPublicationYear "2020" @default.
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