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The kinase AKT1 potentiates the suppressive functions of myeloid-derived suppressor cells in inflammation and cancer

Cellular & Molecular Immunology volume 18, pages 1074–1076 (2021)Cite this article

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Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells1 that play crucial negative regulatory roles in immune-associated diseases, including infections,2 cancer,3 transplantation4, and autoimmunity.5 We and others have shown that mTOR signaling and its downstream metabolic pathways regulate MDSC recruitment and function in inflammation and autoimmunity.5,6,7,8,9 While AKT kinase family members, including ATK1, AKT2, and AKT3, are known downstream targets of mTOR, it is unclear whether any of them plays a role in regulating MDSC functions and metabolism. Herein, we report that AKT1 (also known as protein kinase B α, PKBα) regulates MDSC immunosuppressive activities by suppressing hypoxia-inducible factor 1α (HIF1α)-dependent glycolysis. Genetic ablation of AKT1 significantly impaired MDSC immunosuppressive functions, and concurrent deletion of HIF1α or pharmacological inhibition of glycolytic metabolic activities could partially restore MDSC function in vitro and in various pathological contexts. Our results implicate AKT1 as a critical signaling node that regulates both the metabolic activities and functions of MDSCs in the context of inflammation and cancer.

Akt1−/− mice showed a lower survival curve than WT mice in the murine endotoxic shock model (Fig. S3A). Importantly, hepatic Akt1−/− MDSCs showed reduce suppressive activities and increased levels of hepatic injury markers (Fig. S3B, C). Hepatic Akt1−/− CD11b+Gr1+ MDSCs showed increase TNFα and IL-12 production and reduced IL-10 production (Fig. S3D). Interestingly, adoptive transfer of sorted hepatic CD11b+Gr1+ MDSCs from Akt1−/− but not WT endotoxic shock model mice into WT C57BL/6 recipients significantly reduced endotoxic mouse survival (Fig. 1C) and exacerbated ALT levels (Fig. S4). Collectively, these data suggest that AKT1 is critical for MDSC-mediated protection against inflammatory hepatic injury in murine endotoxic shock.

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Acknowledgements

This research is supported by grants from the National Natural Science Foundation for Key Programs of China (31730024, G.L.), the National Natural Science Foundation for General Programs of China (31671524, G.L.), and the Beijing Municipal Natural Science Foundation of China (5202013, GL).

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  1. These authors contributed equally: Anna Jia, Yuexin Wang, Yufei Wang, Yan Li

Authors and Affiliations

  1. Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China

    Anna Jia, Yuexin Wang, Yufei Wang, Yan Li, Qiuli Yang, Yejin Cao, Ying He, Lin Dong, Yingjie Dong, Yueru Hou & Guangwei Liu

  2. Center for Childhood Cancer & Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Ohio State University, Columbus, OH, 43205, USA

    Ruoning Wang

  3. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China

    Yujing Bi

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Contributions

A.J., Y.B., and Y.X.W. designed and conducted the mouse and cell experiment and analyzed the data; Y.F.W., Y.L., Q.Y. Y.C., Y.H., L.D., Y.D., Y.H., and R.W. participated in discussions; R.W. and Y.B. contributed to writing the manuscript; and G.L. developed the concept, designed and conducted the experiments, analyzed the data, wrote the manuscript, and provided overall direction.

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Correspondence to Ruoning Wang, Yujing Bi or Guangwei Liu.

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The authors declare no competing interests.

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The present study was approved by the Ethics Committee of the College of Life Science of Beijing Normal University, Beijing China.

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Jia, A., Wang, Y., Wang, Y. et al. The kinase AKT1 potentiates the suppressive functions of myeloid-derived suppressor cells in inflammation and cancer. Cell Mol Immunol 18, 1074–1076 (2021). https://doi.org/10.1038/s41423-020-00610-7

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