BACKGROUND Pre-clinical cancer studies ascribe promising anticancer properties to metformin. Yet, clinical findings vary, casting uncertainty on its therapeutic value for non-small cell lung cancer (NSCLC) patients. We hypothesized that metformin could benefit obese and overweight patients with NSCLC. METHODS We retrospectively analyzed two clinical cohorts and employed complementary mouse models to test our hypothesis. One cohort included NSCLC patients with overweight BMI (≥25, n = 511) and non-overweight BMI (<25, n = 232) who underwent lobectomy, evaluating metformin's impact on clinical outcomes. Another cohort examined metformin's effect on progression-free survival (PFS) after immune checkpoint inhibitors (ICI) in overweight (n = 284) vs non-overweight (n = 184) NSCLC patients. Metformin's effects on tumor progression, antitumor immunity, and ICI response in obese and normal-weight mice were assessed with lung cancer models. RESULTS Metformin is associated with increased recurrence-free survival in overweight patients (HR = 0.47 [95%CI = 0.24-0.94], p = .035) after lobectomy. It also corrected accelerated tumor growth in diet-induced obese mouse models in a lymphocyte-specific manner while reversing several mechanisms of immune suppression potentiated by obesity. PD-1 blockade coupled with metformin was more effective at limiting tumor burden in obese mice and correlated with PFS only in overweight patients on immunotherapy (HR = 0.60, [95%CI = 0.39-0.93], p = .024). CONCLUSIONS Metformin may improve lung cancer-specific clinical outcomes in obese and overweight lung cancer patients and enhance immunotherapy efficacy in this growing population as well. This work identifies obesity as a potential predictive biomarker of metformin's anticancer and immunotherapy-enhancing properties in lung cancer while shedding light on the underlying immunological phenomena.

中文翻译：

---

肥胖 - 二甲双胍肺癌结局和免疫治疗效果的特异性改善。


背景 临床前癌症研究认为二甲双胍具有有希望的抗癌特性。然而，临床发现各不相同，对其对非小细胞肺癌 （NSCLC） 患者的治疗价值存在不确定性。我们假设二甲双胍可能有益于肥胖和超重的 NSCLC 患者。方法 我们回顾性分析了两个临床队列，并采用互补小鼠模型来检验我们的假设。一个队列包括接受肺叶切除术的超重 BMI （≥25， n = 511） 和非超重 BMI （<25， n = 232） 的 NSCLC 患者，评估二甲双胍对临床结局的影响。另一个队列检查了二甲双胍对超重 （n = 284） 和非超重 （n = 184） NSCLC 患者免疫检查点抑制剂 （ICI） 后无进展生存期 （PFS） 的影响。用肺癌模型评估二甲双胍对肥胖和正常体重小鼠肿瘤进展、抗肿瘤免疫和 ICI 反应的影响。结果 二甲双胍与肺叶切除术后超重患者无复发生存期增加相关 （HR = 0.47 [95%CI = 0.24-0.94]，p = .035）。它还以淋巴细胞特异性方式纠正了饮食诱导的肥胖小鼠模型中加速的肿瘤生长，同时逆转了肥胖增强的几种免疫抑制机制。PD-1 阻断联合二甲双胍在限制肥胖小鼠的肿瘤负荷方面更有效，并且仅在接受免疫治疗的超重患者中与 PFS 相关 （HR = 0.60，[95%CI = 0.39-0.93]，p = .024）。结论 二甲双胍可能改善肥胖和超重肺癌患者的肺癌特异性临床结局，并提高这一不断增长的人群的免疫治疗效果。 这项工作将肥胖确定为二甲双胍在肺癌中抗癌和免疫治疗增强特性的潜在预测生物标志物，同时阐明潜在的免疫学现象。