Immunotherapy is expected to become the most promising new treatment for ovarian cancer owing to its immunogenicity. However, immunosuppression in the tumor microenvironment is a major obstacle to the efficacy of tumor therapy. Studies have found different metabolism ways of regulatory T cells (Tregs) in the cancer environment may be related to the immunosuppression and Toll-like receptor 8 (TLR8) can reverse the suppression function of Tregs. But it is still unclear that if the TLR8-mediated function reversal is associated with the change of glucose metabolism of Tregs. It was found that the positive expression rates of Glut1, HIF-1α, and Ki67 in CD4⁺ Treg cells of OC were significantly higher than that in benign ovarian tumor and HC, and also significantly higher than that in CD4⁺ Teffs of OC. What’s more, compared with CD4⁺ Teff group, CD4⁺ Tregs highly expressed seven genes and three proteins related to glucose metabolism and had higher levels of glucose uptake and glycolysis. After activating TLR8 signal of CD4⁺ Tregs, the proliferation level of naive CD4⁺ T cells was higher than that of the control group. At the same time, the expression levels of eight genes and five proteins related to glucose metabolism in CD4⁺ Treg cells with TLR8 activated were decreased and levels of glucose uptake and glycolysis were also lower. Furthermore, TLR8 signaling also downregulated the mTOR pathway in CD4⁺ Tregs. CD4⁺ Tregs pretreated with 2-deoxy-d-Glucose (2-DG) and galloflavin also attenuated the inhibition of Teffs proliferation. Although CD4⁺ Tregs pretreated with 2-DG and galloflavin before activating TLR8 signal had no significant difference compared with the group only treated with inhibitors, which suggested TLR8-mediated reversal of CD4⁺ Treg cells inhibitory function in ovarian cancer cells co-cultured microenvironment had a causal relationship with glucose metabolism.

由于其免疫原性，免疫疗法有望成为卵巢癌最有前途的新疗法。然而，肿瘤微环境中的免疫抑制是肿瘤治疗效果的主要障碍。研究发现，癌症环境中调节性T细胞（Tregs）的不同代谢方式可能与免疫抑制有关，Toll样受体8（TLR8）可以逆转Tregs的抑制功能。但目前尚不清楚TLR8介导的功能逆转是否与Tregs糖代谢的变化有关。发现OC的CD4 ⁺ Treg细胞中Glut1、HIF-1α、Ki67的阳性表达率显着高于卵巢良性肿瘤和HC，也显着高于CD4 ⁺OC 的 Teffs。此外，与CD4 ⁺ Teff组相比，CD4 ⁺ Tregs高表达7个与糖代谢相关的基因和3个蛋白，葡萄糖摄取和糖酵解水平更高。激活CD4 ⁺ Tregs的TLR8信号后，幼稚CD4 ⁺ T细胞的增殖水平高于对照组。同时，TLR8激活的CD4 ⁺ Treg细胞中与糖代谢相关的8个基因和5个蛋白的表达水平降低，葡萄糖摄取和糖酵解水平也降低。此外，TLR8 信号还下调 CD4 ⁺ Tregs 中的 mTOR 通路。CD4 ⁺用 2-脱氧-d-葡萄糖 (2-DG) 和鸡黄素预处理的 Tregs 也减弱了对 Teffs 增殖的抑制。尽管在激活 TLR8 信号前用 2-DG 和鸡黄素预处理的CD4 ⁺ Tregs 与仅用抑制剂处理的组相比没有显着差异，这表明 TLR8 介导的卵巢癌细胞共培养微环境中 CD4 ⁺ Treg 细胞抑制功能的逆转具有与葡萄糖代谢的因果关系。