Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA.
J Immunother Cancer. 2021 Nov;9(11). doi: 10.1136/jitc-2021-002614.
PD-L1 is one of the major immune checkpoints which limits the effectiveness of antitumor immunity. Blockade of PD-L1/PD-1 has been a major improvement in the treatment of certain cancers, however, the response rate to checkpoint blockade remains low suggesting a need for new therapies. Metformin has emerged as a potential new drug for the treatment of cancer due to its effects on PD-L1 expression, T cell responses, and the immunosuppressive environment within tumors. While the benefits of metformin in combination with checkpoint blockade have been reported in animal models, little remains known about its effect on other types of immunotherapy.
Vaccine immunotherapy and metformin were administered to mice inoculated with tumors to investigate the effect of metformin and TMV vaccine on tumor growth, metastasis, PD-L1 expression, immune cell infiltration, and CD8 T cell phenotype. The effect of metformin on IFN-γ induced PD-L1 expression in tumor cells was assessed by flow cytometry, western blot, and RT-qPCR.
We observed that tumors that respond to metformin and vaccine immunotherapy combination show a reduction in surface PD-L1 expression compared with tumor models that do not respond to metformin. In vitro assays showed that the effect of metformin on tumor cell PD-L1 expression was mediated in part by AMP-activated protein kinase signaling. Vaccination results in increased T cell infiltration in all tumor models, and this was not further enhanced by metformin. However, we observed an increased number of CD8 T cells expressing PD-1, Ki-67, Tim-3, and CD62L as well as increased effector cytokine production after treatment with metformin and tumor membrane vesicle vaccine.
Our data suggest that metformin can synergize with vaccine immunotherapy to augment the antitumor response through tumor-intrinsic mechanisms and also alter the phenotype and function of CD8 T cells within the tumor, which could provide insights for its use in the clinic.
PD-L1 是主要的免疫检查点之一，限制了抗肿瘤免疫的效果。PD-L1/PD-1 的阻断已成为治疗某些癌症的重大进展，然而，对检查点阻断的反应率仍然很低，表明需要新的治疗方法。二甲双胍因其对 PD-L1 表达、T 细胞反应和肿瘤内免疫抑制环境的影响，已成为治疗癌症的潜在新药。虽然二甲双胍与检查点阻断联合应用的益处已在动物模型中得到报道，但对于其对其他类型免疫疗法的影响知之甚少。
给接种肿瘤的小鼠给予疫苗免疫治疗和二甲双胍，以研究二甲双胍和 TMV 疫苗对肿瘤生长、转移、PD-L1 表达、免疫细胞浸润和 CD8 T 细胞表型的影响。通过流式细胞术、western blot 和 RT-qPCR 评估二甲双胍对 IFN-γ诱导的肿瘤细胞 PD-L1 表达的影响。
我们观察到，与对二甲双胍无反应的肿瘤模型相比，对二甲双胍和疫苗免疫治疗联合治疗有反应的肿瘤显示表面 PD-L1 表达减少。体外实验表明，二甲双胍对肿瘤细胞 PD-L1 表达的影响部分是通过 AMP 激活的蛋白激酶信号传导介导的。接种疫苗导致所有肿瘤模型中 T 细胞浸润增加，而二甲双胍并未进一步增强这种增加。然而，我们观察到在用二甲双胍和肿瘤膜囊泡疫苗治疗后，CD8 T 细胞表达 PD-1、Ki-67、Tim-3 和 CD62L 的数量增加，以及效应细胞因子的产生增加。
我们的数据表明，二甲双胍可以与疫苗免疫治疗协同作用，通过肿瘤内在机制增强抗肿瘤反应，同时改变肿瘤内 CD8 T 细胞的表型和功能，这可为其在临床上的应用提供依据。
