介绍：改善日益增长早期患者库的结果需要开发辅助非手术治疗策略，这些策略传统上集中在晚期非小细胞肺癌。二甲双胍是一种广泛使用的II型188bet在线平台网址 药物，具有长期的安全性和最小的副作用，也被认为具有抗癌活性。我们之前已经证明二甲双胍在I期非小细胞肺癌中的抗癌作用取决于患者体重指数(BMI)。为了深入了解这些环境依赖效应的分子机制，我们试图在小鼠肺癌模型中模拟高BMI状态和二甲双胍的效应。

        Introduction:Improving outcomes for the growing early-stage patient pool requires developing adjuvant non-surgical therapeutic strategies, which have been traditionally focused on late-stage NSCLC. Metformin, a widely used type II diabetes drug with a long history of safety and minimal side effects, is also known to show anti-cancer activity. We have previously demonstrated that the anti-cancer effects metformin in stage I NSCLC is dependent on patient Body mass index (BMI). To gain insight into the molecular mechanism responsible for these context-dependent effects, we sought to model the effects of high-BMI status and metformin in a mouse model of lung cancer.

        方法：通过给C57BL/6小鼠喂食高脂饮食16周，建立饮食诱导肥胖(DIO)，年龄/性别匹配的对照组小鼠以正常饮食喂养。来自肥胖组和非肥胖组的队列皮下注射Lewis肺癌(LLC)细胞，随后进行监测，直到发现已形成的肿瘤为止(~11天)。荷瘤小鼠每两天腹腔注射二甲双胍(50mg/kg)，连续测量肿瘤生长。流式细胞术用于测量肿瘤免疫微环境，RNA-seq用于测量比较人群中肿瘤的基因表达。

        Methods:Diet-induced obesity (DIO) was established by feeding C57BL/6 mice a high-fat diet for 16 weeks. Age/sex-matched control mice were fed a normal diet. Cohorts from obese and non-obese groups were injected subcutaneously with Lewis lung carcinoma (LLC) cells and subsequently monitored until established tumors were noted (~day 11). Tumor-bearing mice were then injected intraperitoneally every two days with metformin (50 mg/kg), and tumor growth was serially measured. Flow cytometry was used to measure tumor immune microenvironment and RNA-seq was used to measure gene expression of tumors in comparison populations.

        结果

图1总结了我们的结果。未服用二甲双胍的肥胖小鼠支持肿瘤的强劲生长。然而，二甲双胍治疗的肥胖小鼠的肿瘤生长受到抑制。相比之下，二甲双胍对非肥胖小鼠的治疗并不影响肿瘤的进展，这与肺部患者的生存数据一致。二甲双胍对肥胖和非肥胖小鼠的免疫检查点分子有不同的影响。特别值得注意的是二甲双胍治疗肥胖小鼠肿瘤相关调节性T细胞PD-1和CTLA-4水平的降低。与非肥胖对照组相比，二甲双胍也降低了肥胖小鼠肿瘤浸润淋巴细胞中表达PD-1的CD8+T细胞的频率。对这些小鼠肿瘤中基因表达的转录组分析也揭示了二甲双胍对与白细胞记忆/效应器分化调节相关的基因编码因子以及在代谢和生物合成途径中具有已知作用的基因的肥胖依赖性影响。

        Results:Figure 1 summarizes our results. Obese mice given no metformin supported robust tumor growth. However, tumor growth was suppressed in metformin-treated obese mice. In contrast, and in agreement with lung patient survival data, metformin treatment of non-obese mice did not affect tumor progression. Immune checkpoint molecules were divergently affected by metformin in obese and non-obese mice. Particularly notable were the reductions seen in the levels of PD-1 and CTLA-4 on tumor-associated regulatory (Treg) T cells in metformin-treated obese mice. The frequencies of PD-1-expressing CD8+ T cells among tumor-infiltrating lymphocytes were also reduced by metformin in obese mice compared to non-obese controls. Transcriptome analysis of gene expression in the tumors of these mice also revealed obesity-dependent effects of metformin on genes encoding factors relevant to the regulation of leukocyte memory/effector differentiation as well as genes with known roles in metabolic and biosynthetic pathways.

        结论：在高BMI患者中观察到的二甲双胍的促生存和抗肿瘤作用是跨物种的，因此可以在广泛使用的小鼠模型中进行机理探讨。研究结果表明，二甲双胍对高BMI肺癌患者和肥胖小鼠的免疫调节作用可能源于独特的代谢条件，这种代谢条件可以提供抗肿瘤免疫反应的最佳重塑。

        Conclusion:Pro-survival and anti-tumor effects of metformin observed in high-BMI patients are operative across species and can therefore be explored mechanistically in widely used mouse models. Our results suggest that the immune-modifying effects of metformin seen in high-BMI lung cancer patients and obese mice alike may stem from unique metabolic conditions that afford optimal reshaping of the anti-tumor immune response.