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Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes

Cellular & Molecular Immunology volume 19, pages 944–956 (2022)Cite this article

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Abstract

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cancer. The effect of glucose metabolism on γδ T cells and their impact on tumor surveillance remain unknown. Here, we showed that high glucose induced Warburg effect type of bioenergetic profile in Vγ9Vδ2 T cells, leading to excessive lactate accumulation, which further inhibited lytic granule secretion by impairing the trafficking of cytolytic machinery to the Vγ9Vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro, in vivo and in patients. Strikingly, activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vγ9Vδ2 T cells. These results suggest that the impaired antitumor activity of Vγ9Vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.

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Additional data collected during this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported in part by Seed Funding for Strategic Interdisciplinary Research Scheme, University of Hong Kong, and the General Research Fund, Research Grants Council of Hong Kong (17122222, 17122519, 17126317), Hong Kong SAR, China. This work was also partly supported by the National Natural Science Foundation of China (32000616), China.

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  1. These authors contributed equally: Xiaofeng Mu, Zheng Xiang.

Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China

    Xiaofeng Mu, Zheng Xiang, Xiwei Wang, Yanmei Zhang, Wenyue Zhang, Wing-hang Leung, Yu-Lung Lau, Yinping Liu & Wenwei Tu

  2. The First Affiliated Hospital, Faculty of Medical Science, Jinan University, Guangzhou, 510632, Guangdong, PR China

    Yan Xu

  3. Zhuhai Precision Medical Center, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China

    Yan Xu & Zhinan Yin

  4. The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China

    Yan Xu, Yuyuan Chen & Zhinan Yin

  5. GuangDong 999 Brain Hospital, Guangzhou City, Guangdong Province, PR China

    Jing He

  6. Department of Endocrinology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China

    Jianwen Lu

  7. Computational and Systems Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, 90095, USA

    Chloe Ran Tu

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Contributions

XM, YL, and WT conceived and designed the study, interpreted the results, and wrote the manuscript. XM, ZX, YX, YC, and XW performed the experiments and analyzed the results with the assistance of CRT, YZ and WZ. JH and JL obtained the patient samples. ZY, WHL, and YLL provided advice, reagents, and critical insight.

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Correspondence to Yinping Liu or Wenwei Tu.

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Mu, X., Xiang, Z., Xu, Y. et al. Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes. Cell Mol Immunol 19, 944–956 (2022). https://doi.org/10.1038/s41423-022-00894-x

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