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Enzymatic depletion of circulating glutamine is immunosuppressive in cancers
Monish Kumar1, Ankita Leekha1, Suman Nandy1
1William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA.
Abstract:
Although glutamine addiction in cancer cells is extensively reported, there is controversy on the impact of glutamine metabolism on the immune cells within the tumor microenvironment (TME). To address the role of extracellular glutamine, we enzymatically depleted circulating glutamine using PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) in syngeneic mouse models of breast and colon cancers. PEG-GGT treatment inhibits growth of cancer cells in vitro, but in vivo it increases myeloid-derived suppressor cells (MDSCs) and has no significant impact on tumor growth. By deriving a glutamine depletion signature, we analyze diverse human cancers within the TCGA and illustrate that glutamine depletion is not associated with favorable clinical outcomes and correlates with accumulation of MDSC. Broadly, our results help clarify the integrated impact of glutamine depletion within the TME and advance PEG-GGT as an enzymatic tool for the systemic and selective depletion (no asparaginase activity) of circulating glutamine in live animals.
Insights
Glutamine depletion inhibits cancer cell growth in vitro but increases myeloid-derived suppressor cells (MDSCs) in vivo. This suggests glutamine metabolism
Area of Science:
- Tumor Microenvironment Immunology
- Cancer Metabolism
- Enzymatic Therapeutics
Background:
- Cancer cells exhibit glutamine addiction, but its impact on tumor microenvironment (TME) immune cells remains debated.
- Extracellular glutamine plays a critical role in TME dynamics.
- Understanding glutamine's role is crucial for developing novel cancer therapies.
Purpose of the Study:
- To investigate the effect of extracellular glutamine depletion on cancer growth and immune cell populations within the TME.
- To evaluate the therapeutic potential of PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) for systemic glutamine depletion.
Main Methods:
- Enzymatic depletion of circulating glutamine using PEG-GGT in syngeneic mouse models of breast and colon cancers.
- In vitro assessment of PEG-GGT's effect on cancer cell growth.
- Analysis of TCGA human cancer data to derive a glutamine depletion signature and correlate it with clinical outcomes and MDSC accumulation.
Main Results:
- PEG-GGT treatment inhibited cancer cell growth in vitro.
- In vivo, PEG-GGT treatment increased myeloid-derived suppressor cells (MDSCs) without significantly impacting tumor growth.
- A glutamine depletion signature correlated with unfavorable clinical outcomes and MDSC accumulation across diverse human cancers.
Conclusions:
- Extracellular glutamine depletion has a complex impact on the TME, promoting MDSC accumulation.
- PEG-GGT is a promising tool for selective systemic glutamine depletion, offering a novel therapeutic strategy.
- Findings clarify the integrated role of glutamine metabolism in cancer and immunity.
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