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

Mu, Xiaojing; Xiang, Zheng; Xu, Yan; He, Jing; Lu, Jianwen; Chen, Yu-Yuan; Wang, Xiwei; Tu, Chloe Ran; Zhang, Yanmei; Zhang, Wenyue; Yin, Zhinan; Leung, Wing-Hang; Lau, Yu Lung; Liu, Yinping; Tu, Wenwei

doi:10.1038/s41423-022-00894-x

Cited by 15 publications

(10 citation statements)

References 72 publications

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“…These favorable results might be explained by selection of highly motivated and compliant patients for monitoring insulin levels; however, the results of animal models suggest that controlling insulin levels supports to the anti-tumor effects of alpelisib 15 and thus controlling hyperinsulinemia might have contributed to the beneficial oncological outcomes of our patients. A recent study suggested that hyperglycemia suppresses T cell anti- tumor effects 23 and PI3K inhibition increased anti- tumor immune response in a study using mouse models of metastatic breast cancer. 24 Recent evidence highlights the role of mitochondrial metabolism in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer – A Real-Life Experience

Percik¹,

Smith²,

Leibovici³

et al. 2023

BTT

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PIK3CA activating mutations are found in 40% of advanced breast cancer and are associated with worse prognosis. PI3K blockage is associated with insulin resistance, leading to hyperglycemia and hyperinsulinemia. Alpelisib is the first PI3K inhibitor used in cancer treatment. Laboratory evidence indicated that alpelisib-induced hyperinsulinemia offsets the drug’s efficacy, but insulin levels were not tested in the clinical trials that evaluated alpelisib for breast cancer. Hyperglycemia could also interfere with anti-tumor effects of PI3K inhibitors by inducing Immune tolerance and altered mitochondrial metabolism. We have monitored insulin levels in 4 breast cancer patients with concomitant metabolic syndrome treated with alpelisib, and pre-treated patients with baseline increased insulin levels with pioglitazone, a potent insulin sensitizer, to target both hyperinsulinemia and hyperglycemia, and we report the treatment course of these patients. All patients achieved glycemic control and were able to maintain alpelisib dose intensity. Duration of response to alpelisib was longer than anticipated in this treatment setting. Insulin dynamics confirmed the efficacy of pioglitazone as a specific on-target hypoglycemic and hypo-insulinemic agent in the unique setting of PI3K blockade. Our experience suggests that targeting hyperinsulinemia in patients with is safe and feasible and results in good metabolic and oncologic outcomes.

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Section: Discussionmentioning

confidence: 99%

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer – A Real-Life Experience

Percik¹,

Smith²,

Leibovici³

et al. 2023

BTT

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“…In ICI-resistant tumor cells, a similarity between cells with ICI resistance and a hypermetabolic phenotype was observed. This phenotype included synergistic upregulation of glycolysis and mitochondrial oxidative phosphorylation, which assists tumor cells in maintaining vigorous growth under hypoxia and resisting ICT [ 195 , 224 ]. The associations between checkpoint molecules related to the internal metabolism of tumor cells and ICs is also an interesting topic [ 225 ].…”

Section: Future Perspectivementioning

confidence: 99%

Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment

et al. 2023

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As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.

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“…[68,69] In a study published in Cellular and Molecular Immunology in August 2022, scientists from the University of Hong Kong, China, found that a high level of glucose might increase the risk of cancer in diabetic patients by inhibiting the antitumor activity of the body's gd T cells. [70] Moreover, glucose-controlled metabolic reprogramming might improve the antitumor activity of gd T cells. This study showed that the number and antitumor activity of gd T cells in diabetic patients were significantly deficient.…”

Section: High Levels Of Glucose Impair the Antitumor Activity Of Gd T...mentioning

confidence: 99%

γδ T cells: Major advances in basic and clinical research in tumor immunotherapy

Zhao,

Dong,

et al. 2023

Chinese Medical Journal

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γδ T cells are a kind of innate immune T cell. They have not attracted sufficient attention because they account for only a small proportion of all immune cells, and many basic factors related to these cells remain unclear. However, in recent years, with the rapid development of tumor immunotherapy, γδ T cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex (MHC) restriction. An increasing number of basic studies have focused on the development, antigen recognition, activation, and antitumor immune response of γδ T cells. Additionally, γδ T cell-based immunotherapeutic strategies are being developed, and the number of clinical trials investigating such strategies is increasing. This review mainly summarizes the progress of basic research and the clinical application of γδ T cells in tumor immunotherapy to provide a theoretical basis for further the development of γδ T cell-based strategies in the future.

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

Cited by 15 publications

References 72 publications

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer – A Real-Life Experience

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer – A Real-Life Experience

Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment

γδ T cells: Major advances in basic and clinical research in tumor immunotherapy

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