1. Global alteration of T-lymphocyte metabolism by PD-L1 checkpoint involves a block of de novo nucleoside phosphate synthesis
- Author
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Palaskas, Nicolaos Jay, Garcia, Jacob David, Shirazi, Roksana, Shin, Daniel Sanghoon, Puig-Saus, Cristina, Braas, Daniel, Ribas, Antoni, and Graeber, Thomas Glen
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Immunotherapy ,Cancer ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Cancer microenvironment ,DNA metabolism ,Metabolomics ,RNA metabolism ,Tumour immunology ,Biochemistry and cell biology - Abstract
Metabolic obstacles of the tumor microenvironment remain a challenge to T-cell-mediated cancer immunotherapies. To better understand the interplay of immune checkpoint signaling and immune metabolism, this study developed and used an optimized metabolite extraction protocol for non-adherent primary human T-cells, to broadly profile in vitro metabolic changes effected by PD-1 signaling by mass spectrometry-based metabolomics and isotopomer analysis. Inhibitory signaling reduced aerobic glycolysis and glutaminolysis. A general scarcity across the panel of metabolites measured supported widespread metabolic regulation by PD-1. Glucose carbon fate analysis supported tricarboxylic acid cycle reliance on pyruvate carboxylation, catabolic-state fluxes into acetyl-CoA and succinyl-CoA, and a block in de novo nucleoside phosphate synthesis that was accompanied by reduced mTORC1 signaling. Nonetheless, exogenous administration of nucleosides was not sufficient to ameliorate proliferation of T-cells in the context of multiple metabolic insufficiencies due to PD-L1 treatment. Carbon fate analysis did not support the use of primarily glucose-derived carbons to fuel fatty acid beta oxidation, in contrast to reports on T-memory cells. These findings add to our understanding of metabolic dysregulation by PD-1 signaling and inform the effort to rationally develop metabolic interventions coupled with immune-checkpoint blockade for increased treatment efficacy. more...
- Published
- 2019