Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial

Wang, Shuhong; Lin, Yusheng; Xiong, Xi; Wang, Lu; Guo, Yi; Chen, Yuping; Chen, Shaobin; Wang, Geng; Lin, Peng; Chen, Hongcai; Yeung, Sai‐Ching Jim; Bremer, Edwin; Zhang, Hao

doi:10.1158/1078-0432.ccr-20-0113

Cited by 100 publications

(76 citation statements)

References 46 publications

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“…The response to cancer immunotherapy especially immune checkpoint inhibitors were impacted by tumor immune microenvironment. Wang et al found that an "infiltrated-excluded" or "cole" tumor immune microenvironment is predictive of poor response and low-dose metformin reprograms the TME in ESCC [17]. Research by Strizova et al showed that FasR + NK cells, CD4 + , and CD8 + T cells infiltrated lymph nodes at the lowest levels and that the FasR + DR3 + CD4 + T cells were enhanced in esophageal cancer [18].…”

Section: Discussionmentioning

confidence: 99%

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

Liu

et al. 2021

BMC Med Genomics

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Background As a complex system participating in tumor development and progression, the tumor microenvironment was poorly understood in esophageal cancer especially squamous cell carcinoma (ESCC). Methods ESTIMATE algorithm is used to investigate tumor-infiltrating immune cells and prognostic genes which were associated with the tumor microenvironment in ESCC. Results Based on the immune and stromal scores, ESCC samples were divided into high and low score groups and 299 overlapping differentially expressed genes were identified. Functional enrichment analysis showed that these genes were mainly involved in muscle-related function. Prognostic genes including COL9A3, GFRA2, and VSIG4 were used to establish a risk prediction model using Cox regression analyses. Then multivariate analysis showed that COL9A3 was an independent discriminator of a better prognosis. Kaplan–Meier survival analysis showed that the expression of COL9A3 was significantly correlated with the overall survival of ESCC patients. The area under the curve for the risk model in predicting 1- and 3- year survival rates were 0.660 and 0.942, respectively. The risk score was negatively correlated with plasma cells, while positively correlated with the proportions of activated CD4 memory T cells, M1 Macrophages and M2 Macrophages (p < 0.001 for each comparison). Gene set enrichment analysis suggested that both immune response and immune system process gene sets were significantly enriched in high-risk group. Conclusions Our study provided a comprehensive understanding of the TME in ESCC patients. The establishment of the risk model is valuable for the early identification of high-risk patients to facilitate individualized treatment and improve the possibility of immunotherapy response.

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Section: Discussionmentioning

confidence: 99%

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

Liu

et al. 2021

BMC Med Genomics

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“…Additionally, silencing KLF10 repressed γ-H2AX and p-DNApkcs expression. Metformin, a well-known drug for diabetes, has been reported to improve the response to therapy and reprogram the tumour immune microenvironment in OSCC [35]. Metformin can induce KLF10 expression via AMPK and increase the radiosensitivity of pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

Chen

et al. 2021

J Exp Clin Cancer Res

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Background Radiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communication between hypoxic cells and aerobic cells via exosomes during the transfer of radiation resistance remains unclear. Methods Exo-miR-340-5p levels were analysed by RNA-seq and qRT-PCR. We co-cultured OSCC cells with isolated normoxic and hypoxic exosomes to study their impact on radiosensitivity. We used a specific exo-miR-340-5p mimic and knock-down retrovirus to explore the role of this miRNA in the transfer of radioresistance from hypoxic to normoxic cells. Dual-luciferase reporter and RIP assays were used to verify KLF10 as a putative target of miR-340-5p. Several in vitro assays were conducted and xenograft models were established to investigate the effect of exo-miR-340-5p on OSCC radiosensitivity. The plasma exo-miR-340-5p levels in OSCC patients were analysed to study the clinical value of this parameter. Results Hypoxic exosomes alleviated radiation-induced apoptosis and accelerated DNA damage repair. miR-340-5p was highly expressed in hypoxic exosomes and was transferred into normoxic cells, where it induced radioresistance. Overexpression of miR-340-5p in normoxic OSCC cells mimicked the radioresistance of cells co-cultured with hypoxic exosomes. Knockdown of miR-340-5p in hypoxic exosomes reversed the radioresistance effect, indicating that exo-miR-340-5p is critical for hypoxic EV-transferred radioresistance. KLF10 was identified as the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance the radiosensitivity of OSCC. Higher levels of miR-340-5p in the plasma exosomes from OSCC patients are related to a poorer radiotherapy response and prognosis. Conclusions Hypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Metformin can increase KLF10 expression, which ameliorates the radioresistance induced by exo-miR-340-5p transfer. Therefore, metformin could be further investigated as a therapeutic option for the treatment of OSCC.

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“…Besides, We also explored the relationship between our model risk score and immune cell infiltration. The tumor immune microenvironment contains a variety of immune cells including dendritic cell, natural killer cell, macrophage, T and B lymphocyte, all of which can affect the efficacy of ICIs ( 47 ). However, we only concluded that the immune differential gene risk score related to prognosis was negatively correlated with B cell infiltration in ESCC.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Novel Risk Score System of Immune Genes Associated With Prognosis in Esophageal Carcinoma

et al. 2021

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BackgroundFew studies have addressed the role of immune-related genes in the survival and prognosis of different esophageal cancer (EC) sub-types. We established two new prognostic model indexes by bioinformatics analysis to select patients with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) who may benefit from immunotherapy.MethodsBased on TCGA and ImmPort data sets, we screened immune genes differentially expressed between tumor and normal tissues in ESCC and EAC and analyzed the relationship between these genes and patient survival outcomes. We established the risk score models of immune-related genes in ESCC and EAC by multivariate COX regression analysis.ResultsWe identified 12 and 11 immune-related differentially expressed genes associated with the clinical prognosis of ESCC and EAC respectively, based on which two prognostic risk score models of the two EC sub-types were constructed. It was found that the survival probability of patients with high scores was significantly lower than that of patients with low scores (p < 0.001). BMP1, EGFR, S100A12, HLA-B, TNFSF18, IL1B, MAPT and OXTR were significantly related to sex, TNM stage or survival outcomes of ESCC or EAC patients (p < 0.05). In addition, the risk score of ESCC was significantly correlated with the level of B cell infiltration in immune cells (p < 0.05).ConclusionsThe prognosis-related immune gene model indexes described herein prove to be useful prognostic biomarkers of the two EC sub-types in that they may provide a reference direction for looking for the beneficiaries of immunotherapy for EC patients.

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Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial

Cited by 100 publications

References 46 publications

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

Establishment of a Novel Risk Score System of Immune Genes Associated With Prognosis in Esophageal Carcinoma

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