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.

BackgroundGrowing evidence suggests that SALL4 plays a vital role in tumor progression and metastasis. However, the molecular mechanism of SALL4 promoting esophageal squamous cell carcinoma (ESCC) remains to be elucidated.MethodsThe gene and protein expression profiles- were examined by using quantitative real-time PCR, immunohistochemistry and western blotting. Small hairpin RNA was used to evaluate the role of SALL4 both in cell lines and in animal models. Cell proliferation, apoptosis and invasion were assessed by CCK8, flow cytometry and transwell-matrigel assays. Sphere formation assay was used for cancer stem cell derivation and characterization.ResultsOur study showed that the transcription factor SALL4 was overexpressed in a majority of human ESCC tissues and closely correlated with a poor outcome. We established the lentiviral system using short hairpin RNA to knockdown SALL4 in TE7 and EC109 cells. Silencing of SALL4 inhibited the cell proliferation, induced apoptosis and the G1 phase arrest in cell cycle, decreased the ability of migration/invasion, clonogenicity and stemness in vitro. Besides, down-regulation of SALL4 enhanced the ESCC cells’ sensitivity to cisplatin. Xenograft tumor models showed that silencing of SALL4 decreased the ability to form tumors in vivo. Furthermore, our study demonstrated that SALL4 played a vital role in modulating the stemness of ESCC cells via Wnt/β-catenin signaling pathway and in epithelial-mesenchymal transition.ConclusionsOur results revealed that SALL4 might serve as a functional marker for ESCC cancer stem cell, a crucial marker for prognosis and an attractive candidate for target therapy of ESCC.

Complex interactions between the immune system and tumor cells exist throughout the initiation and development of cancer. Although the immune system eliminates malignantly transformed cells in the early stage, surviving tumor cells evade host immune defense through various methods and even reprogram the anti-tumor immune response to a pro-tumor phenotype to obtain unlimited growth and metastasis. The high proliferation rate of tumor cells increases the demand for local nutrients and oxygen. Poorly organized vessels can barely satisfy this requirement, which results in an acidic, hypoxic, and glucose-deficient tumor microenvironment. As a result, lipids in the tumor microenvironment are activated and utilized as a primary source of energy and critical regulators in both tumor cells and related immune cells. However, the exact role of lipid metabolism reprogramming in tumor immune response remains unclear. A comprehensive understanding of lipid metabolism dysfunction in the tumor microenvironment and its dual effects on the immune response is critical for mapping the detailed landscape of tumor immunology and developing specific treatments for cancer patients. In this review, we have focused on the dysregulation of lipid metabolism in the tumor microenvironment and have discussed its contradictory roles in the tumor immune response. In addition, we have summarized the current therapeutic strategies targeting lipid metabolism in tumor immunotherapy. This review provides a comprehensive summary of lipid metabolism in the tumor immune response.

MicroRNAs are an important regulator for T cell immune response. In this study, we aimed to identify microRNAs with the potential to regulate T cell differentiation. The influence of miR-143 on differentiation and function of CD8 T cells from healthy donors were detected, and it was found that miR-143 overexpression could significantly increase the differentiation of central memory T (Tcm) CD8 cells, decrease cell apoptosis, and increase proinflammatory cytokine secretion. Furthermore, the specific killing of HER2-CAR T cells against esophageal cancer cell line TE-7 was enhanced by miR-143 overexpression. Glucose transporter 1 (Glut-1) was identified as the critical target gene of miR-143 in the role of T cell regulation. By inhibition Glut-1, miR-143 inhibited glucose uptake and glycolysis in T cell to regulated T cell differentiation. Tcm cell populations were also suppressed in parallel with the downregulation of miR-143 in tumor tissues from 13 patients with esophagus cancer. IDO and its metabolite kynurenine in the tumor microenvironment were screened as an upstream regulator of miR-143. IDO small interfering RNA significantly increased the expression of miR-143 and Tcm cell population. In conclusion, our results show that miR-143 enhanced antitumor effects of T cell by promoting memory T cell differentiation and metabolism reprogramming through Glut-1. Our findings will encourage the development of new strategies targeting miR-143 in both cancer cells and T cells.

PD‐1 is highly expressed on tumor‐infiltrated antigen‐specific T cells and limit the antitumor function. Blocking of PD‐1/PD‐L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE‐A3‐specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE‐A3‐specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE‐A3‐specific CD8+ T cells could lyse HLA‐A2+/MAGE‐A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD‐1 was highly expressed on dysfunctional antigen‐specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid‐derived suppressor cells (MDSCs) derived‐TGF‐β mediated PD‐1high expression on CD8+ T cells, which led to be resistance to PD‐1/PD‐L1 blockade in TME. Dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockades synergistically restored the function and antitumor ability of antigen‐specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE‐A3‐specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs‐derived TGF‐β increased PD‐1 expression on T cells and decreased the sensitivity to PD‐1/PD‐L1 blockade. Combining T cell‐based therapy with dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockade could be considered a promising strategy for cancer treatment.

: Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. : We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured. To study MDSC chemotaxis, BALB/C nude mice were injected subcutaneously with TE7 cells and treated with metformin. Migration of adoptively transferred MDSCs was analyzed using flow cytometry and immunohistochemistry. : The frequency of tumor-infiltrated polymorphonuclear (PMN)-MDSCs was increased compared to their circulating counterparts. There was a significant correlation between PMN-MDSCs accumulation in tumors and ESCC prognosis. Moreover, PMN-MDSCs displayed immunosuppressive activity. Treatment with metformin reduced MDSC migration in patients. Metformin inhibited CXCL1 secretion in ESCC cells and tumor xenografts by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-κB inhibition and reducing MDSC migration. Knockdown of AMPK and DACH1 expression blocked the effect of metformin on MDSC chemotaxis. : A novel anti-tumor effect of metformin, which is mediated by reducing PMN-MDSC accumulation in the tumor microenvironment via AMPK/DACH1/CXCL1 axis.

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Esophageal cancer is currently one of the most fatal cancers. However, there is no effective treatment. Increasing evidence suggests that interleukin (IL)‐33 has a significant role in tumor progression and metastasis. Currently, the underlying cellular and molecular mechanism of IL‐33 in promoting esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we investigated whether IL‐33 could induce the epithelial‐mesenchymal transition (EMT) in ESCC. Interleukin‐33 expression was examined in ESCC and corresponding adjacent normal tissues by immunohistochemistry and quantitative real‐time PCR experiments. Elevated IL‐33 levels were observed in ESCC tissues. Further in vitro experiments were undertaken to elucidate the effect of IL‐33 on migration and invasion in KYSE‐450 and Eca‐109 esophageal cancer cells. Knockdown of IL‐33 decreased the metastasis and invasion capacity in esophageal cancer cells, whereas IL‐33 overexpression showed the opposite effect. We then screened CCL2 which is a downstream molecule of IL‐33, and proved that IL‐33 could promote tumor development and metastasis by recruiting regulatory T cells (Tregs) through CCL2, and IL‐33 regulated the expression of CCL2 through transforming growth factor‐β in Treg cells. Knockdown of IL‐33 decreased the development of human ESCC xenografts in BALB/c nude mice. Collectively, we found that the IL‐33/nuclear factor‐κB/CCL2 pathway played an essential role in human ESCC progress. Hence, IL‐33 should be considered as an effective therapy target for ESCC.