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Integrated Metabolomic and Transcriptomic Profiling Reveals Novel Activation-Induced Metabolic Networks in Human T cells

ABSTRACT:

The targeting of metabolic pathways is emerging as an exciting new approach for modulating immune cell function and polarization states. In this study, carbon tracing and systems biology approaches integrating metabolomic and transcriptomic profiling data were used to identify adaptations in human T cell metabolism important for fueling pro-inflammatory T cell function. Results of this study demonstrate that T cell receptor (TCR) stimulation leads to a significant increase in glucose and amino acid metabolism that trigger downstream biosynthetic processes. Specifically, increased expression of several enzymes such as CTPS1, IL4I1, and ASL results in the reprogramming of amino acid metabolism. Additionally, the strength of TCR signaling resulted in different metabolic enzymes utilized by T cells to facilitate similar biochemical endpoints. Furthermore, this study shows that cyclosporine represses the pathways involved in amino acid and glucose metabolism, providing novel insights on the immunosuppressive mechanisms of this drug. To explore the implications of the findings of this study in clinical settings, conventional immunosuppressants were tested in combination with drugs that target metabolic pathways. Results showed that such combinations increased efficacy of conventional immunosuppressants. Overall, the results of this study provide a comprehensive resource for identifying metabolic targets for novel combinatorial regimens in the treatment of intractable immune diseases.

INSTRUMENT(S): Liquid Chromatography MS - Negative (LC-MS (NEG)), Liquid Chromatography MS - Positive (LC-MS (POS))

SUBMITTER: Shashank Jatav

PROVIDER: MTBLS926 | MetaboLights | 2024-04-03

REPOSITORIES: MetaboLights

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Project description:Cancer immunosuppression involves cellular pathways appropriated by tumors to escape immune surveillance but are normally required for tissue homeostasis and repair, self-tolerance, and successful transplantation. Among these pathways, enzymes that degrade tryptophan and arginine are thought to suppress activated T cells in the tumor microenvironment and are therefore attractive drug targets. However, how amino acid metabolism controls the development and progression of cancer has remained elusive, since commonly used implantable tumor models may not faithfully recapitulate the complex cellular and biochemical interactions within tumor microenvironments. To address this, we generated a novel, penetrant autochthonous model of neuroblastoma to accurately quantify tumor growth non-invasively and simultaneously genetically manipulate the enzymes that mediate tryptophan and arginine metabolism, and the cells that express them. We established that tumor development and growth were dependent on infiltrating CCR2+ bone marrow-derived myeloid cells but independent of Stat6-dependent ‘M2’ macrophages. Macrophages can modulate CD4+ T cell activation, proliferation, and differentiation by consuming amino acids and forcing the T cells to remain in the G1 phase of the cell cycle. Indeed, we found that CD4+ T cells deprived of arginine increased Foxp3 expression and adopted a unique regulatory-like phenotype. Notably, depletion of CD4+ T cells like CCR2+ macrophages, virtually eliminated tumor formation. When rare tumors did form in CD4-depleted mice, they contained Foxp3+ CD8 T cells, suggesting regulatory T cell activity is a fundamental requirement for tumor development. When we ablated macrophage arginase 1 (Arg1), an enzyme that locally consumes arginine, in the tumor-prone background, almost no tumors were observed. Therefore, Arg1 and arginine metabolism form a pro-tumor pathway. We extended these findings to two pathways of programmed myeloid tryptophan metabolism (IDO1, IDO2, IL4i1). Like Arg1, expression of these enzymes was confined to myeloid cells in humans and mice, and each enzyme was independently essential for tumor formation and growth. The protective effects of genetic ablation of each myeloid amino acid pathways uniformly occurred early in tumor formation, arguing that a network of immune cells controlled by myeloid amino acid metabolism and CD4+ T cells is important for the origins of a pro-tumor environment. Our results establish an unappreciated potency of macrophage amino acid metabolism in promoting malignancy, and suggest that these pathways can be disabled by targeting of myeloid amino acid metabolism. OVA-specific CD4+ T cells were stimulated with peptide in the presence of APCs (CD3-depleted splenocytes) either in control complete RPMI-1640 (containing 10% dialyzed FBS) or in RPMI-1640 (containing 10% dialyzed FBS) containing 1% of the normal arginine levels (12uM) to characterize the effects of limited arginine availability on gene expression.

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Integrated Metabolomic and Transcriptomic Profiling Reveals Novel Activation-Induced Metabolic Networks in Human T cells

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