Endocr Relat Cancer. 2018 Apr;25(4):493-507. doi: 10.1530/ERC-17-0529. Epub 2018 Feb 19.
Diabetic patients have higher incidence and mortality of cancer. Recent study revealed that hyperglycemia-induced oxidative stress is involved in the acceleration of tumor metastasis. We used model of high-dose streptozotocin-induced diabetes to investigate its effect on tumor growth and modulation of antitumor immune response of 4T1 murine breast cancer in BALB/c mice. Diabetes accelerated tumor appearance, growth and weight, which was associated with decreased NK cells cytotoxicity against 4T1 tumor cells Diabetes reduced frequencies of systemic NKG2D, perforin, granzyme, IFN-γ and IL-17 NK cells, while increased level of PD-1 expression and production of IL-10 in NK cells. Diabetes decreased percentage of NKG2DNK cells and increased percentage of PD-1 NK cells also in primary tumor. Diabetes increased accumulation of IL-10 Tregs and TGF-β myeloid-derived suppressor cells (MDSCs) in spleen and tumor. Diabetic sera significantly increased the percentage of KLRG-1 and PD-1 NK cells, decreased the percentage of IFN-γNK cells, expression of NKp46 and production of perforin, granzyme, CD107a and IL-17 per NK cell in comparison to glucose-added mouse sera and control sera. Significantly increased percentages of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO) producing MDSCs and dendritic cells (DC) were found in the spleens of diabetic mice prior to tumor induction. 1--DL-, specific IDO inhibitor, almost completely restored phenotype of NK cells cultivated in diabetic sera. These findings indicate that diabetes promotes breast cancer growth at least in part through increased accumulation of immunosuppressive cells and IDO-mediated attenuation of NK cells.
糖尿病患者癌症的发病率和死亡率更高。最近的研究表明，高血糖诱导的氧化应激参与了肿瘤转移的加速。我们使用高剂量链脲佐菌素诱导糖尿病模型，研究其对 BALB/c 小鼠 4T1 鼠乳腺癌肿瘤生长和抗肿瘤免疫反应的调节作用。糖尿病加速了肿瘤的出现、生长和体重增加，这与 NK 细胞对 4T1 肿瘤细胞的细胞毒性降低有关。糖尿病降低了 NK 细胞中系统 NKG2D、穿孔素、颗粒酶、IFN-γ 和 IL-17 的频率，而增加了 PD-1 表达和 IL-10 的产生。糖尿病也降低了原发性肿瘤中 NKG2DNK 细胞的百分比，并增加了 PD-1 NK 细胞的百分比。糖尿病增加了 IL-10 Treg 和 TGF-β 髓系来源抑制细胞（MDSC）在脾脏和肿瘤中的积累。糖尿病血清与添加葡萄糖的小鼠血清和对照血清相比，显著增加了 KLRG-1 和 PD-1 NK 细胞的百分比，降低了 IFN-γNK 细胞的百分比，NK 细胞表达 NKp46 和穿孔素、颗粒酶、CD107a 和 IL-17 的产生。在诱导肿瘤之前，糖尿病小鼠脾脏中发现诱导型一氧化氮合酶（iNOS）和吲哚胺 2,3-双加氧酶（IDO）产生的 MDSC 和树突状细胞（DC）的百分比显著增加。1--DL-，一种特定的 IDO 抑制剂，几乎完全恢复了在糖尿病血清中培养的 NK 细胞的表型。这些发现表明，糖尿病至少部分通过增加免疫抑制细胞的积累和 IDO 介导的 NK 细胞衰减来促进乳腺癌的生长。
