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mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells

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Abstract

Immune cell activation occurs concurrently with metabolic reprogramming. As important components of the tumor microenvironment, monocytic myeloid-derived suppressor cells (M-MDSCs) are featured by their potent immunosuppressive abilities on anti-tumor effector cells. However, little is known about the contribution of metabolic adaptations to their suppressive roles. In this study, we found that tumor-infiltrating M-MDSCs had the same phenotype with splenic M-MDSCs. Compared with splenic M-MDSCs, tumor-infiltrating M-MDSCs exhibited stronger suppressive activities which was accompanied by higher glycolysis. Inhibition of glycolysis impaired the suppressive function of tumor M-MDSCs. Meanwhile, the results demonstrated that mTOR was responsible for this function regulation. mTOR inhibition by rapamycin decreased the glycolysis and reduced the suppressive activities of these cells. Furthermore, rapamycin treatment inhibited the tumor growth and reduced the percentage of M-MDSCs in 3LL tumor bearing mice. These results demonstrated that modulation of metabolism in immune cells can be an effective way to enhance anti-tumor effects.

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Abbreviations

2-DG:

2-Deoxy-d-glucose

2NBDG:

2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose

Arg1:

Arginase I

ECAR:

Extracellular acidification rate

Eno1:

Enolase 1

FMO:

Fluorescence minus one

HK2:

Hexokinase 2

Glut1:

Glucose transporter 1

Gpi:

Glucose-6-phosphate isomerase

LC/MS:

Liquid chromatography–mass spectrometry

Ldha:

Lactate dehydrogenase A

Mct4:

Monocarboxylate transporter 4

mTOR:

Mammalian target of rapamycin

NOS2:

Nitric oxide synthase 2

OCR:

Oxygen consumption rate

PD-L1:

Programmed death ligand 1

Pkm2:

Pyruvate kinase muscle isozyme

TCA cycle:

Tricarboxylic acid cycle

Tpi:

Triosephosphate isomerase

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Funding

This work was supported by the National Natural Science Foundation of China under Grants 31570892, 81730045 and 91527305.

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Author notes

  1. Yuting Deng and Jiao Yang contributed equally to this manuscript and should be considered as co-first authors.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, People’s Republic of China

    Yuting Deng, Jiao Yang, Feifei Luo, Jing Qian, Ronghua Liu, Dan Zhang & Yiwei Chu

  2. Biotherapy Research Center, Fudan University, Shanghai, China

    Yuting Deng, Jiao Yang, Feifei Luo, Dan Zhang & Yiwei Chu

  3. Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China

    Feifei Luo

  4. Department of Systems Biology for Medicine, School of Basic Medical Sciences and Institute of Biomedical Sciences, Fudan University, Shanghai, China

    Hongxiu Yu

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Contributions

Conception and design: YC, YD and JY; development of methodology: YD, JY and FL; acquisition of data: YC, YD, JY, FL, JQ, HY, DZ and RL; analysis and interpretation of data: YC, YD, JY and FL; writing, review, and/or revision of the manuscript: YC, YD, JY, FL and RL. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Yiwei Chu.

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Conflict of interest

The authors declare that they have no conflict of interest. 3LL Lewis Lung Carcinoma cells were purchased from the Cell Bank of Type Culture Collection of Chinese Academy of Sciences. C57BL/6 mice were purchased from the Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China).

Animal rights

All experiments were approved by the Institutional Animal Care and Use Committee of Fudan University (20140226067) following the Guidelines for the Care and Use of Laboratory Animals (No. 55 issued by Ministry of Health, China on January 25th, 1998).

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Deng, Y., Yang, J., Luo, F. et al. mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells. Cancer Immunol Immunother 67, 1355–1364 (2018). https://doi.org/10.1007/s00262-018-2177-1

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