Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer

Li, Lifeng; Wang, Liping; Li, Jieyao; Fan, Zhirui; Li, Yang; Zhang, Zhen; Zhang, Chaoqi; Yue, Dongli; Qin, Guohui; Zhang, Tengfei; Li, Feng; Chen, Xinfeng; Yü, Ping; Wang, Dan; Gao, Qun; He, Qianyi; Huang, Lan; Li, Hong; Huang, Jianmin; Zhao, Xuan; Xue, Wenhua; Sun, Zhi; Lü, Jingli; Yu, Jane; Zhao, Jie; Zhang, Bin; Zhang, Yi

doi:10.1158/0008-5472.can-17-2460

Cited by 204 publications

(150 citation statements)

References 61 publications

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“…Of these, the majority were excluded after the first screening based on their abstracts or titles, mainly because they were in vitro studies and not case-control or cohort studies, or because the exposure or endpoint was not relevant to our analysis, leaving 18 potentially eligible papers for full-text review. After full-text review of 18 papers, five articles were excluded for the following reasons: no data to calculate OR, RR, or HR,20 or no inclusion of ovarian cancer 21–24. Consequently, 13 articles were included in this meta-analysis.…”

Section: Resultsmentioning

confidence: 99%

Association of metformin use with ovarian cancer incidence and prognosis: a systematic review and meta-analysis

Shi

Liu

Wang

et al. 2019

Int J Gynecol Cancer

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BackgroundSome clinical and basic research studies have indicated that exposure to metformin might have protective effects against ovarian cancer. However, results from epidemiologic studies have been inconsistent. We performed a meta-analysis to evaluate the effect of metformin use on the risk of ovarian cancer occurrence and mortality.MethodsMultiple databases were searched to identify studies on the association between use of metformin and risk of ovarian cancer or prognosis, up to August 2018. Relevant information for analysis was extracted. A random-effects model was used to calculate the pooled risk estimate.ResultsThirteen articles were included, of which six articles focused on ovarian cancer incidence and the others focused on prognosis. The pooled OR for ovarian cancer occurrence and mortality comparing metformin use with non-use or use of other hypoglycemic drugs was 0.76 (95% CI 0.62 to 0.93, p = 0.008) and 0.55 (95% CI 0.36 to 0.84, p = 0.006), respectively. Moderate to substantial heterogeneity was observed across included studies.ConclusionsOur findings demonstrate that use of metformin was significantly associated with a lower incidence and a better prognosis of ovarian cancer in patients with diabetes. Well-designed interventional studies are warranted to confirm our findings.

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Section: Resultsmentioning

confidence: 99%

Association of metformin use with ovarian cancer incidence and prognosis: a systematic review and meta-analysis

Shi

Liu

Wang

et al. 2019

Int J Gynecol Cancer

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“…Myeloid-derived suppressor cells (MDSCs) play pivotal roles in promoting tumor progression and contribute to immunosuppressive function (Ostrand-Rosenberg, 2010;Li et al, 2018e). MDSCs are a heterogeneous group of pathologically activated immature myeloid cells in the TME.…”

Section: Myeloid Derived Suppressor Cellsmentioning

confidence: 99%

T Cell Dysfunction and Exhaustion in Cancer

Zhang

et al. 2020

Front. Cell Dev. Biol.

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233

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Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.

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“…Metformin reduces PD‐L1 expression on cancer cells, rendering susceptible to the recognition by tumor‐infiltrating T lymphocytes . In cancer patients, metformin reduces the expression and ectoenzymatic activity of CD39 and CD73 on myeloid derived suppressor cells . CD39 and CD73 can participate in an immunosuppressive pathway that leads to the degradation of the (immunostimulatory) pool of extracellular ATP to the immunosuppressive metabolite adenosine.…”

Section: Conclusion Limitations and Perspectivesmentioning

confidence: 99%

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

Sica

Pedro

Stoll

et al. 2019

Intl Journal of Cancer

131

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In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate—or at least are compatible with—anticancer immune responses for long‐term tumor control.

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Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer

Cited by 204 publications

References 61 publications

Association of metformin use with ovarian cancer incidence and prognosis: a systematic review and meta-analysis

Association of metformin use with ovarian cancer incidence and prognosis: a systematic review and meta-analysis

T Cell Dysfunction and Exhaustion in Cancer

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

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