L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity

By R. Geiger, J. Rieckmann, Tobias Wolf, C. Basso, Yuehan Feng, Tobias Fuhrer, Maria Kogadeeva, Paola Picotti, F. Meissner, Matthias Mann and 3 more. Cell, 2016

1,537 citations recorded by the source corpus.

Summary Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses.

Subfields: Biotechnology, Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/e1fb98c2ec2dcb49cc13d61d7f670b506cd721bf

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Citations in the corpus

The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “For example, L-Arg is required for the expression of the CD3ζ chain and therefore crucial for TCR signaling and cytotoxicity (217, 218).”
Metabolic Instruction of Immunity (2017, positive): “Several recent studies have highlighted the critical roles of other amino acids such as arginine, serine, and glycine in driving T cell expansion and antitumor activity, but how the availability of these fluctuate within the tumor microenvironment is not clear (Geiger et al., 2016; Ma et al., 2017).”
Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “CD8+ T cells especially benefit from L-arginine uptake by enhanced survival, memory formation and anti-tumor efficacy (Geiger et al., 2016).”
Metabolic Interactions in the Tumor Microenvironment (2017, background): “enhances the bioenergetic profile of T cells, leading to a central memory like T cell state and improved anti-tumor activity [88].”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “For example, arginine has important roles in T cell function 181 , and competition with cancer cells and other cells of the TME for this amino acid might result in suppression of the antitumour activity of T cells.”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Recent studies indicate that L-arginine has an important role in regulating T cell metabolism, as supplementation of the culture medium with L-arginine resulted in decreased protein expression of glycolytic enzymes, while Krebs cycle and serine biosynthetic pathway enzyme expression was increased (G”
Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity (2020, background): “We observed metabolic signatures enriched with CD that have been correlated with T cell activation, including sugar and amino acid metabolism (Figure 3K; Geiger et al., 2016; MacIver et al., 2013; Sinclair et al., 2013;Wei et al., 2017).”
Understanding the intersections between metabolism and cancer biology (2017, neutral): “High arginine levels promote enhanced T cell survival and anti-tumor activity (Geiger et al., 2016), and therapies that Cell.”