Department of General Surgery, The First Affiliated Hospital of Jinan University, and Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, China.
Shantou University Medical College, Shantou, Guangdong, China.
Clin Cancer Res. 2020 Sep 15;26(18):4921-4932. doi: 10.1158/1078-0432.CCR-20-0113. Epub 2020 Jul 9.
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).
We analyzed matched pre- and posttreatment 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.
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 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., TNFα, IFNγ, and IL10) in the immune cells.
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.
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反应有重要影响。具体来说，“浸润排斥”/“冷”TIME 预测反应不佳。抗糖尿病药物二甲双胍可能影响食管鳞状细胞癌（ESCC）的抗癌免疫。
我们分析了低剂量二甲双胍（250mg/天）治疗的 II 期临床试验中 ESCC 标本的配对治疗前后标本，以评估其对 ESCC 的直接抗肿瘤活性和 TIME 重编程作用。使用致癌物诱导的 ESCC 小鼠模型进行了后续的相关性研究，采用短期（1 周）或长期（12 周）低剂量二甲双胍（50mg/kg/天）治疗。
在临床试验中，Ki67 和 cleaved caspase-3 免疫染色检测显示，低剂量二甲双胍对 ESCC 肿瘤的增殖或凋亡没有影响。然而，二甲双胍将 TIME 重编程为“浸润性炎症”，并增加浸润的 CD8 细胞毒性 T 淋巴细胞和 CD20 B 淋巴细胞的数量。此外，观察到肿瘤抑制性（CD11c）巨噬细胞增加和肿瘤促进性（CD163）巨噬细胞减少。二甲双胍增强了巨噬细胞对 ESCC 细胞的吞噬作用。在 ESCC 小鼠模型中，短期二甲双胍治疗以类似于人类的方式重编程 TIME，而长期治疗则进一步使 TIME 向活跃状态转变（例如，CD4 FoxP3 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 激活和 STAT3 失活，并改变免疫细胞中效应细胞因子（即 TNFα、IFNγ 和 IL10）的产生。
低剂量二甲双胍重编程 TIME 至激活状态，可能是 ESCC 患者进一步研究的合适免疫反应调节剂。
