Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial
Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial
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低剂量二甲双胍重新编程人类食管癌的肿瘤免疫微环境：II 期临床试验结果
DOI：
10.1158/1078-0432.ccr-20-0113
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发表时间：
2020-09-15
影响因子：
11.5
通讯作者：
Zhang, Hao
中科院分区：
文献类型：
--
作者：
Wang, Shuhong;Lin, Yusheng;Zhang, Hao
目的：肿瘤免疫微环境（TIME）对使用免疫检查点抑制剂的癌症免疫治疗的反应具有重要影响。具体而言，“渗透-排除”/“冷”TIME预测反应不良。抗糖尿病药物二甲双胍可能会影响食管鳞状细胞癌（ESCC）的抗癌免疫力。实验设计：我们分析了匹配的治疗前和治疗后ESCC标本的第二阶段临床试验的低剂量二甲双胍治疗（250毫克/天），以评估直接抗ESCC活性和时间重编程。使用致癌物诱导的ESCC小鼠模型进行了短期（1周）或长期（12周）低剂量二甲双胍（50 mg/kg/day）治疗的后续相关研究。结果：在临床试验中，低剂量二甲双胍不影响ESCC肿瘤的增殖或凋亡，通过Ki 67和切割的caspase-3免疫染色测定。而二甲双胍使TIME向“浸润-炎症”方向改变，并增加浸润的CD 8（+）细胞毒性T淋巴细胞和CD 20（+）B淋巴细胞的数量。此外，观察到肿瘤抑制性（CD 11 c（+））巨噬细胞增加和肿瘤促进性（CD 163（+））巨噬细胞减少。二甲双胍增强巨噬细胞介导的体外食管鳞癌细胞吞噬作用。在ESCC小鼠模型中，短期二甲双胍治疗以与人类相似的方式重新编程TIME，而长期治疗进一步将TIME向活跃状态转移（例如，CD 4（+）FoxP 3（+）调节性T细胞减少）并抑制ESCC生长。在人和小鼠中，二甲双胍触发AMPK活化和STAT 3失活，并改变效应细胞因子的产生（即，结论：低剂量二甲双胍将TIME重新编程为激活状态，可能是一种合适的免疫应答调节剂，可用于ESCC患者的进一步研究。
Purpose: The tumor immune microenvironment (TIME) has an important impact on response to cancer immunotherapy using immune checkpoint inhibitors. Specifically, an "infiltrated-excluded"/"cold" TIME is predictive of poor response. The antidiabetic agent metformin may influence anticancer immunity in esophageal squamous cell carcinoma (ESCC).Experimental Design: We analyzed matched pre- and post-treatment ESCC specimens in a phase II clinical trial of low-dose metformin treatment (250 mg/day) to evaluate direct anti-ESCC activity and TIME reprogramming. Follow-up correlative studies using a carcinogen-induced ESCC mouse model were performed with short-term (1 week) or long-term (12 weeks) low-dose metformin (50 mg/kg/day) treatment.Results: In the clinical trial, low-dose metformin did not affect proliferation or apoptosis in ESCC tumors as assayed by Ki67 and cleaved caspase-3 immunostaining. However, metformin reprogrammed the TIME toward "infiltrated-inflamed" and increased the numbers of infiltrated CD8(+) cytotoxic T lymphocyte and CD20(+) B lymphocyte. Further, an increase in tumor-suppressive (CD11c(+)) and a decrease in tumor-promoting (CD163(+)) macrophages were observed. Metformin augmented macrophage-mediated phagocytosis of ESCC cells in vitro. In the ESCC mouse model, short-term metformin treatment reprogrammed the TIME in a similar fashion to humans, whereas long-term treatment further shifted the TIME toward an active state (e.g., reduction in CD4(+) FoxP3(+) regulatory T cells) and inhibited ESCC growth. In both humans and mice, metformin triggered AMPK activation and STAT3 inactivation, and altered the production of effector cytokines (i.e., TNF alpha, IFN gamma, and IL10) in the immune cells.Conclusions: Low-dose metformin reprograms the TIME to an activated status and may be a suitable immune response modifier for further investigation in patients with ESCC.