Disrupting a converging metabolic target turns up the immunologic-heat in pancreatic tumors
Won Jin Ho, Elizabeth M. Jaffee
Won Jin Ho, Elizabeth M. Jaffee
Published December 3, 2019
Citation Information: J Clin Invest. 2020;130(1):71-73. https://doi.org/10.1172/JCI133685.
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Commentary

Disrupting a converging metabolic target turns up the immunologic-heat in pancreatic tumors

Abstract

Pancreatic ductal adenocarcinomas (PDACs) are classically immunologically cold tumors that have failed to demonstrate a significant response to immunotherapeutic strategies. This feature is attributed to both the immunosuppressive tumor microenvironment (TME) and limited immune cell access due to the surrounding stromal barrier, a histological hallmark of PDACs. In this issue of the JCI, Sharma et al. employ a broad glutamine antagonist, 6-diazo-5-oxo-l-norleucine (DON), to target a metabolic program that underlies both PDAC growth and hyaluronan production. Their findings describe an approach to converting the PDAC TME into a hot TME, thereby empowering immunotherapeutic strategies such as anti-PD1 therapy.

Authors

Won Jin Ho, Elizabeth M. Jaffee

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Figure 1

Targeting a point of convergence in metabolic pathways in PDAC.

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Targeting a point of convergence in metabolic pathways in PDAC. Glutamin...
Glutamine is involved as a substrate for the anaerobic metabolic processes whereby the tricarboxylic acid (TCA) cycle uses glucose to enable effective PDAC cell growth. Glutamine is also a substrate for the rate-limiting enzyme GFAT, which is part of the HBP that acts via uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and leads to hyaluronan synthesis. Thus, glutamine antagonism with DON may reduce both cancer growth and stromal barrier production.