PDF(Pubmed)
Abstract：
Modulation of immune cell metabolism is one of promising strategies to improve cancer immunotherapies. Metformin is an anti-diabetic drug with potential anti-cancer effects, ranging from normalization of blood glucose and insulin levels, direct anti-proliferative effects on cancer cells to emerging immunomodulatory effects on anti-tumor immunity. Metformin can reduce tumor hypoxia and PD-L1 expression, as well as normalize or improve T cell function and potentiate the effect of immune checkpoint inhibitors, making it a promising adjuvant to immunotherapy of tumors with poor response such as triple negative breast cancer (TNBC). However, although the effects of metformin on cancer cells are glucose-dependent, the role of glucose in modulating its effect on T cells has not been systematically studied. We thus investigated the effect of metformin as a function of glucose level on Jurkat cell and PBMC T cell models in vitro. While low metformin concentrations had little effect on T cell function, high concentration reduced proliferation and IFN-γ secretion in both models and induced a shift in T cell populations from memory to effector subsets. The PD-1/CD69 ratio was improved by high metformin in T cells from PBMC. Low glucose and metformin synergistically reduced PD-1 and CD69 expression and IFN-γ secretion in T cells from PBMC. Low glucose level itself suppressed Jurkat cell function due to their limited metabolic plasticity, but had limited effects on T cells from PBMC apart from reduced proliferation. Conversely, high glucose did not strongly affect either T cell model. Metformin in combination with glycolysis inhibitor 2-deoxy-D-glucose (2DG) reduced PD-1 in Jurkat cells, but also strongly suppressed their function. However, low, physiologically achievable 2DG concentration itself reduced PD-1 while mostly maintaining IL-2 secretion and, interestingly, even strongly increased IFN-γ secretion regardless of glucose level. Overall, glucose metabolism can importantly influence some of the effects of metformin on T cell functionality in the tumor microenvironment. Additionally, we show that 2DG could potentially improve the anti-tumor T cell response.
摘要：
调节免疫细胞代谢是改善癌症免疫疗法的有希望的策略之一。二甲双胍是一种具有潜在抗癌作用的抗糖尿病药物，从血糖和胰岛素水平正常化，直接对癌细胞的抗增殖作用，以对抗肿瘤免疫产生免疫调节作用。二甲双胍可降低肿瘤缺氧和PD-L1表达,以及正常化或改善T细胞功能，增强免疫检查点抑制剂的作用，使其成为反应不良的肿瘤，如三阴性乳腺癌（TNBC）的免疫治疗的有希望的佐剂。然而,尽管二甲双胍对癌细胞的作用是葡萄糖依赖性的，葡萄糖在调节其对T细胞的作用中的作用尚未得到系统研究。因此，我们在体外研究了二甲双胍作为葡萄糖水平的函数对Jurkat细胞和PBMCT细胞模型的影响。而低浓度的二甲双胍对T细胞功能影响不大,高浓度会降低两种模型中的增殖和IFN-γ分泌，并诱导T细胞群体从记忆转移到效应子亚群。来自PBMC的T细胞中的高二甲双胍改善了PD-1/CD69比率。低葡萄糖和二甲双胍协同降低PBMCT细胞中的PD-1和CD69表达和IFN-γ分泌。低葡萄糖水平本身抑制Jurkat细胞功能，由于其有限的代谢可塑性，但除了减少增殖外，对PBMC的T细胞的影响有限。相反，高糖对两种T细胞模型均无明显影响.二甲双胍联合糖酵解抑制剂2-脱氧-D-葡萄糖（2DG）降低Jurkat细胞的PD-1，但也强烈抑制了它们的功能。然而,低,生理上可达到的2DG浓度本身会降低PD-1，同时主要维持IL-2的分泌，有趣的是,甚至强烈增加IFN-γ分泌与葡萄糖水平无关。总的来说,二甲双胍对肿瘤微环境中T细胞功能的影响具有重要意义。此外,我们表明2DG可能潜在地改善抗肿瘤T细胞应答。
