Impact of drugs targeting tumor metabolism on human CD8 T cell effector functions

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Cancer and leukemia cells display a strongly elevated glucose and glutamine metabolism and altered mitochondrial function compared to normal cells. The inhibition of those vital metabolic pathways diminishes the proliferation and viability of cancer cells and the secretion of immunosuppressive metabolites. Recent studies, however, suggest that the metabolic phenotype of activated immune cells, especially of T cells, shows similarities to that of cancer cells. Hence the application of drugs inhibiting metabolic pathways considered as essential for both cell types might impede endogenous and therapeutically induced immune responses, thereby adversely affecting patient outcome. However, the interaction between metabolism and effector functions of CD8+ T cells is not well elucidated, particularly in the human system. In the proposed project we will initially characterize the metabolic phenotype of primary human CD8+ T cell subsets (naïve, central memory, effector memory) and in vitro generated leukemia-reactive CD8+ cytotoxic T lymphocytes (CTL) in detail. Furthermore, we will analyze the impact of glycolytic inhibition by diclofenac or monocarboxylate transporter 1/2, mitochondrial inhibition by metformin or pioglitazone, and tyrosine kinase inhibition by sorafenib on effector functions of the aforementioned CD8+ T cell populations in vitro. The in vivo impact on effector functions of human leukemia-reactive CD8+ CTL will be investigated in leukemia bearing NSG mice, with main focus on the most promising and clinically relevant drug candidates. The major objective of the proposed project is the detailed characterization of the interaction between metabolically active drugs and human CD8+ T cell function. The results should allow the identification of immunosuppressive interactions but also potential synergisms in order to improve the effectivity of cancer therapies.