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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion
Open accessAbstract
A fresh look at glutamine targeting: Glutamine is essential for tumor growth and has long been an attractive therapeutic target for cancer researchers. Some attempts at blocking glutamine metabolism in cancer patients resulted in toxicity, prompting Leone et al. to develop an innovative approach to reduce general side effects. They designed a prodrug form (JHU083) of the glutamine antagonist 6-diazo-5-oxo- l -norleucine (DON), which is administered in an inert state but then preferentially activated by enzymes enriched in the tumor microenvironment. JHU083 simultaneously shut down glycolysis and oxidative phosphorylation in mouse cancer cells while enhancing T cell oxidative phosphorylation and anticancer immune responses. Science , this issue p. 1013
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“A recent study discovered a prodrug (JHU083) of the glutamine antagonist DON, which was designed to selectively become activated inside a tumor.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [200]
In the citing paper
“The researchers showed that blocking glutamine metabolism through JHU083 not only suppressed tumor cell metabolism but also mitigated the tumor microenvironment, which is hostile to the immune response due to its hypoxic, acidic, and nutrient-depleted conditions, unleashing the natural antitumor T cell response.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [200]
In the citing paper
“They also confirmed that concurrent treatment with JHU083 and anti-PD-1 checkpoint inhibitor improved the antitumor effects compared with anti-PD-1 treatment alone, suggesting the presence of metabolic plasticity between cancer cells and effector T cells, which could be exploited as a metabolic checkpoint for cancer immunotherapy200.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [200]
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“recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting203, including an orally available analog with promising pre-clinical results in murine PDAC models204”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [203]
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ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses
Kaymak, I., Watson, M. J., Oswald, B. M., Ma, S., Johnson, B. K., DeCamp, L. M., Mabvakure, B. M., Luda, K. M., Ma, E. H., Lau, K. H., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231820 · Cited by 53
“ACSS2 has previously been shown to be expressed by tumor-infiltrating lymphocytes under conditions of glutamine depletion (Leone et al., 2019).”
From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape
Jiang, M., Wang, Y., Zhao, X., & Yu, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1492050 · Cited by 54
“By inhibiting key enzymes such as glutaminase (GLS), not only is tumor cell biosynthesis blocked, but T cell function may also be enhanced, offering a new perspective for tumor immunotherapy (116, 117).”
T cell metabolism in homeostasis and cancer immunity
Wei, J., Zheng, W., Chapman, N. M., Geiger, T. L., & Chi, H. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2021.02.003 · Cited by 52
“Accordingly, blocking glutamine metabolism in the TME enhances oxidative metabolism and SRC, driving CD8+ T cells to adopt a long-lasting stem cell-like state that is associated with superior antitumor responses [63,64].”
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“Transcriptomes of OT-I T cells activated in the presence of Famin / compared to Famin DC supernatants were enriched for hallmark gene sets (Leone et al., 2019) indicative of elevated effector function (Figures 6B, 6C, S6D, and S6E; Table S6).”
BackgroundThe immunometabolic ecosystem in cancer
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Immunometabolism in the Tumor Microenvironment
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Neutrophil metabolism in the cancer context
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“In addition, the same drug induced T cell activation and survival, and blocked glycolytic and oxidative metabolism in cancer cells from several syngeneic tumor models [130].”
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“Notably, this immune modula ory effect of glutamine metab lism bl ckade was also demonstrated in studies using a new y developed pr drug of DON, JHU083, against colon cancer, lymphom , and melanoma, in which JHU083 treatment showed synergistic effects with immune checkpoi t blo kade therapy [51,52].”
BackgroundResultGlycolysis in tumor microenvironment as a target to improve cancer immunotherapy
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“Due to the concerted requirement for the glucose, glutamine and serine metabolic network, improving uptake of one metabolite alone may be insufficient to fully restore T cell function in the TME 20 .”
Cancer immunometabolism: advent, challenges, and perspective
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“Of interest, JHU083 was able to synergize with immunotherapy to enhance infiltration, proliferation, activation, and function of effector T cells in tumors [52].”
BackgroundTargeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer
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“In addition, ample evidence suggests that glutamine plays an essential role in tumors by affecting multiple factors, including the tumor microenvironment, immune evasion, underlying cancer genetics and other variables [36,37].”
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“Thus, the survival of the mice reached almost 100% when the molecule was associated with anti-PD1 or anti-PDL1 antibody treatment [165,166].”
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“In TNBC, the rapid proliferation of tumor cells consumes a large amount of glutamine, thereby depriving glutamate uptake of lymphocytes and affecting the anti-tumor activity of T cells [10].”
BackgroundTargeting cancer-specific metabolic pathways for developing novel cancer therapeutics
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“The simultaneous targeting of glycolysis and glutaminolysis is now emerging as a potential therapeutic strategy for managing a broad range of cancers including breast cancer (60, 179, 180).”
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“Recent findings indicate that tumors can impair glucose homeostasis (31,32), sleep quality (33), and T-cell function (34).”
BackgroundSebestyén, A. R., Dankó, T., Sztankovics, D., Moldvai, D., Raffay, R. E., Cervi, C., Krencz, I., Zsiros, V., Jeney, A., & Petővári, G. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-10006-2 · Cited by 48
“Moreover, immune checkpoint inhibitors or other monoclonal antibody therapies promoted the attempts of glutamine utilization inhibitor (including mTORIs) combinations with pembrolizumab, nivolumab, or daratumumab in advanced solid cancers (NCT04265534 and NCT02771626) [397].”
Background
Metadata
- Authors
- Leone, R. D., Zhao, L., Englert, J. M., Sun, I.-M., Oh, M.-H., Sun, I.-H., Arwood, M. L., Bettencourt, I. A., Patel, C. H., Wen, J., Tam, A., Blosser, R. L., Prchalova, E., Alt, J., Rais, R., Slusher, B. S., & Powell, J. D.
- Affiliations
- Johns Hopkins University (US)
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
- Corresponding author
- Powell, Jonathan D.
- ORCID
- Venue
- Science
- Published
- 2019-11-22
- Volume
- 366
- Issue
- 6468
- Pages
- 1013-1021
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7023461
- OpenAlex
- W2985764787
- Cited by
- 1,169
- References
- 57
- Citations by year
- 2026: 143 · 2025: 196 · 2024: 195 · 2023: 181 · 2022: 197 · 2021: 160 · 2020: 92 · 2019: 4
- FWCI
- 35.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH Office of the Director (R01CA226765, R01CA229451)
- The Bloomberg∼Kimmel Institute for Cancer Immunotherapy.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- glutamine antagonist, tumor immune evasion, tumor microenvironment, cancer metabolism, oxidative metabolism, glycolysis, tumor hypoxia, tumor acidosis, effector T cells, antitumor immunity, metabolic checkpoint, cancer immunotherapy
- MeSH terms
- Animals, Azo Compounds, Caproates, Citric Acid Cycle, Energy Metabolism, Female, Glucose, Glutamine, Immunologic Memory, Lymphocyte Activation, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Tumor Escape, Tumor Microenvironment
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