Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells ( SignificanceThe antitumor activity of an anti-diabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells.

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Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.

Background Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD). Methods We used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo. Results GBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8 + T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo. Conclusions GBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8 + T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD. Electronic supplementary material The online version of this article (10.1186/s12943-019-1027-x) contains supplementary material, which is available to authorized users.

Hypoxia mediates a metabolic switch from oxidative phosphorylation to glycolysis and increases glycogen synthesis. We previously found that glycogen branching enzyme (GBE1) is downstream of the hypoxia-inducible factor-1 (HIF1) signaling pathway in lung adenocarcinoma (LUAD) cells; however, the molecular mechanism underlying HIF1 regulation of GBE1 expression remains unknown. Herein, the effect of GBE1 on tumor progression via changes in metabolic signaling under hypoxia in vitro and in vivo was evaluated, and GBE1-related genes from human specimens and data sets were analyzed. Hypoxia induced GBE1 upregulation in LUAD cells. GBE1-knockdown A549 cells showed impaired cell proliferation, clone formation, cell migration and invasion, angiogenesis, tumor growth, and metastasis. GBE1 mediated the metabolic reprogramming of LUAD cells. The expression of gluconeogenesis pathway molecules, especially fructose-1,6-bisphosphatase (FBP1), was markedly higher in shGBE1 A549 cells than it was in the control cells. FBP1 inhibited the tumor progression of LUAD. GBE1-mediated FBP1 suppression via promoter methylation enhanced HIF1α levels through NF-κB signaling. GBE1 may be a negative prognostic biomarker for LUAD patients. Altogether, hypoxia-induced HIF1α mediated GBE1 upregulation, suppressing FBP1 expression by promoter methylation via NF-κB signaling in LUAD cells. FBP1 blockade upregulated HIF1α, triggered the switch to anaerobic glycolysis, and enhanced glucose uptake. Therefore, targeting HIF1α/GBE1/NF-κB/ FBP1 signaling may be a potential therapeutic strategy for LUAD.