Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer

Edwards, Deanna N.; Ngwa, Verra M.; Raybuck, Ariel; Wang, Shan; Hwang, Young Sil; Kim, Laura C.; Cho, Sung Hoon; Paik, Yeeun; Wang, Qingfei; Zhang, Siyuan; Manning, H. Charles; Rathmell, Jeffrey C.; Cook, Rebecca S.; Boothby, Mark; Chen, Jin

doi:10.1172/jci140100

Cited by 161 publications

(121 citation statements)

References 78 publications

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“…A 'glutamine steal' hypothesis has been proposed in which cancer cell-selective glutamine blockade eliminates metabolic competition in the TME and frees glutamine for use by immune cells [72]. However, the inhibitors used in the studies described above are not selective for cancer cells, raising the question of how glutamine antagonism enhances immune cell function while simultaneously disabling tumor cells.…”

Section: Glutamine Blockade Restores Antitumor Immunitymentioning

confidence: 99%

Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy

et al. 2021

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Section: Glutamine Blockade Restores Antitumor Immunitymentioning

confidence: 99%

Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy

et al. 2021

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“…One exceptional example is that pharmacological inhibition of glutamine uptake using the glutamine transporter inhibitor, V-9302, selectively blocked glutamine uptake by triple-negative breast cancer cells but not CD8+ T cells. Interestingly, CD8+ T cells use a compensatory pathway to upregulate an alternative glutamine transporter, SLC6A14, and sustain glutamine uptake and effector function in V-9302-treated tumors (96).…”

Section: Manipulating the Amino Acid Transporters For Cancer Immunotherapy Inhibiting The Slc Transporters For The Treatment Of Cancersmentioning

confidence: 99%

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment

et al. 2021

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Cancer cells are metabolically vigorous and are superior in the uptake of nutrients and in the release of the tumor microenvironment (TME)-specific metabolites. They create an acidic, hypoxic, and nutrient-depleted TME that makes it difficult for the cytotoxic immune cells to adapt to the metabolically hostile environment. Since a robust metabolism in immune cells is required for optimal anti-tumor effector functions, the challenges caused by the TME result in severe defects in the invasion and destruction of the established tumors. There have been many recent developments in NK and T cell-mediated immunotherapy, such as engineering them to express chimeric antigen receptors (CARs) to enhance tumor-recognition and infiltration. However, to defeat the tumor and overcome the limitations of the TME, it is essential to fortify these novel therapies by improving the metabolism of the immune cells. One potential strategy to enhance the metabolic fitness of immune cells is to upregulate the expression of nutrient transporters, specifically glucose and amino acid transporters. In particular, the amino acid transporters SLC1A5 and SLC7A5 as well as the ancillary subunit SLC3A2, which are required for efficient uptake of glutamine and leucine respectively, could strengthen the metabolic capabilities and effector functions of tumor-directed CAR-NK and T cells. In addition to enabling the influx and efflux of essential amino acids through the plasma membrane and within subcellular compartments such as the lysosome and the mitochondria, accumulating evidence has demonstrated that the amino acid transporters participate in sensing amino acid levels and thereby activate mTORC1, a master metabolic regulator that promotes cell metabolism, and induce the expression of c-Myc, a transcription factor essential for cell growth and proliferation. In this review, we discuss the regulatory pathways of these amino acid transporters and how we can take advantage of these processes to strengthen immunotherapy against cancer.

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“…For example, the glutamine transporter inhibitor V-9302 selectively inhibits glutamine uptake by tumor, but not CD8 + T, cells. CD8 + T cells can regulate glutamine metabolism by upregulating glutamine transporter ATB 0,+ /Slc6a14 ( 69 ). The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) and its precursor, JHU-083, inhibit tumor metabolism and have a strong antitumor effect.…”

Section: Tumor Glutamine Metabolism and Immune Escapementioning

confidence: 99%

“…Different drugs that target glutamine metabolism may have different effects on immune cells in TME. For example, JHU-083 and V-9302 inhibit glutamine metabolism in T eff cells, but T cells regulate their own metabolism via different mechanisms without affecting their antitumor function ( 69 , 70 ). Therefore, in addition to the combination of imaging technology and isotope labeling technology to solve the above mentioned problems, the development of more reasonable drugs that target glutamine metabolism without affecting or enhancing the function of T eff cells on the basis of the difference in glutamine metabolism between tumor and T eff cells is the focus of future research.…”

Section: Strategies Targeting Glucose or Glutamine Metabolism In Combination With Pd-1/pd-l1 Checkpoint Blockade Immunotherapy For Tumor mentioning

confidence: 99%

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies

Zhang

et al. 2021

Front. Oncol.

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Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

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Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer

Cited by 161 publications

References 78 publications

Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy

Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies

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