HKUMed discovers glucose control may improve the antitumour activity of γδ-T cells in diabetes

A research team at LKS Faculty of Medicine, The University of Hong Kong (HKUMed) discovered that high glucose impairs the antitumour activity of immune effector γδ-T cells¹, which contributes to the increased cancer risk in diabetes and that metabolic reprogramming by glucose control may improve the antitumour activity of γδ-T cells. This study provides novel therapeutic targets for enhancing the antitumour immunity of γδ-T cells and further reducing the risk of tumour development and progression in diabetes. The discovery has been published in the leading academic journal, Cellular & Molecular Immunology [link to the publication].

Background
As the ninth major cause of death worldwide², diabetes and its related comorbidities greatly burden the global economy and health care systems. Approximately 10% of adults worldwide have diabetes mellitus, and more than 90% have type 2 diabetes mellitus (T2DM). Diabetes is associated with increased incidence and mortality for many types of cancers, including pancreatic, liver, breast, colorectal, and endometrial cancer. Since elevated blood glucose can stimulate cancer cell proliferation and progression, hyperglycemia may contribute to the high risk of developing cancers in diabetes. In addition, the high cancer risk is also thought to be associated with abnormal immunity because glucose metabolism is critical for the proliferation, differentiation, and function of immune cells and shaping the immune response. While γδ-T cells play an essential role in tumour immunosurveillance, the impact of hyperglycemia on immunosurveillance and cancer risk in diabetes is not well understood.

Recently, we showed that the phosphoantigen pamidronate³-activated human γδ-T cells and their exosomes⁴ could efficiently kill tumour cells by secreting cytotoxic effectors and control tumour growth. These characteristics of γδ-T cells make them promising candidates for cancer immunotherapy. However, whether and how glucose metabolism affects the antitumour effects of γδ-T cells remains unknown.

Research findings
Herein, the research team found that high glucose induced a high level of lactate production and secretion in γδ-T cells, which in turn prevented the trafficking of the cytolytic machinery to the γδ-T-cell-tumour synapse and impaired the antitumour activity of γδ-T cells.

‘Our study demonstrated for the first time that diabetes have both quantitative and qualitative defects in γδ-T cells in terms of number and cytotoxicity against tumour cells. Thus, defects in γδ-T cells may contribute to the high cancer risk in diabetes. We further elucidate a fundamental mechanism associated with γδ-T-cell defects in diabetes. Strikingly, we found that metabolic reprogramming by glucose control or metformin treatment can reverse metabolic abnormalities and restore the antitumour activity of γδ-T cells induced by high glucose. The results highlight glucose metabolic pathways as targets to reverse immune defects in diabetes and suggest that metabolic reprogramming by glucose control or metformin treatment may improve the antitumour activity of γδ-T cells to prevent the development of cancer in diabetes’ said Professor Tu Wenwei of the Department of Paediatrics and Adolescent Medicine, School for Clinical Medicine, HKUMed, who led the research.

Significance of the study
The findings of the study have significant implications for controlling and preventing the development of cancer in diabetes. This study elucidates for the first time that dysregulated glucose metabolism induces the defective cytotoxicity of γδ-T cells against tumour cells in diabetes. And, metabolic reprogramming by glucose control or metformin treatment can restore the antitumour activity of γδ-T cells, which may provide novel therapeutic targets for enhancing the antitumour immunity of γδ-T cells and further reducing the risk of tumour development and progression in diabetes.

About the research team
The research was led by Professor Tu Wenwei, Antony and Nina Chan Professor in Paediatric Immunology, Department of Paediatrics and Adolescent Medicine, School for Clinical Medicine, HKUMed. Dr Mu Xiaofeng and Dr Xiang Zheng, post-doctoral fellows of Professor Tu’s team, are the first authors. Other researchers include Dr Wang Xiwei, post-doctoral fellow, Zhang Yanmei and Zhang Wenyue, PhD students; Xu Yan, post-doctoral fellow and Chen Yuyuan, MPhil of Professor Yin Zhinan’s team in the Biomedical Translational Research Institute, Jinan University, China; Dr He Jing, GuangDong 999 Brain Hospital, China; Dr Lu Jianwen, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, China; Chloe Ran Tu, Computational and Systems Biology Interdepartmental Program, University of California, Los Angeles, California, the United States; Professor Leung Wing-hang, Chairperson and Clinical Professor; Professor Lau Yu-lung, Doris Zimmern Professor in Community Child Health and Chair Professor of Paediatrics; Dr Liu Yinping, Research Officer, Department of Paediatrics and Adolescent Medicine, School for Clinical Medicine, HKUMed.

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

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medmedia@hku.hk).

¹ γδ-T cell is an important component of immune effector cells that contribute to tumour immunosurveillance against many types of tumors, such as lymphoma, myeloma, hepatocellular, and colorectal carcinoma, and prostate, lung, colon, breast, and ovary cancers.
² Reference: Zheng, Y., Ley, S. H. & Hu, F. B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14, 88-98, doi:10.1038/nrendo.2017.151 (2018).
³ Phosphoantigen pamidronate commonly used for the treatment of osteoporosis;
⁴ Exosomes are endosome-originated small extracellular vesicles (20 to 200 nm) that shuttle lipids, proteins, and nucleic acids among cells as a form of intercellular communication.