Department of Medical Oncology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, HV Amsterdam, The Netherlands.
Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Oncoimmunology. 2019 Jul 19;8(10):e1631119. doi: 10.1080/2162402X.2019.1631119. eCollection 2019.
In patients with cancer, the functionality of Dendritic Cells (DC) is hampered by high levels of tumor-derived suppressive cytokines, which interfere with DC development and maturation. Poor DC development can limit the efficacy of immune checkpoint blockade and vaccination approaches. Interference in intracellular signaling cascades downstream from the receptors of major tumor-associated suppressive cytokines like IL-10 and IL-6, might improve DC development and activation, and thus enhance immunotherapy efficacy. We performed exploratory functional screens on arrays consisting of >1000 human kinase peptide substrates to identify pathways involved in DC development and its inhibition by IL-10 or IL-6. The resulting alterations in phosphorylation of the kinome substrate profile pointed to glycogen-synthase kinase-3β (GSK3β) as a pivotal kinase in both DC development and suppression. GSK3β inhibition blocked human DC differentiation , which was accompanied by decreased levels of IL-12p70 secretion, and a reduced capacity for T cell priming. More importantly, adenoviral transduction of monocytes with a constitutively active form of GSK3β induced resistance to the suppressive effects of IL-10 and melanoma-derived supernatants alike, resulting in improved DC development, accompanied by up-regulation of co-stimulatory markers, an increase in CD83 expression levels in mature DC, and diminished release of IL-10. Moreover, adenovirus-mediated intratumoral manipulation of this pathway in an melanoma model resulted in DC activation and recruitment, and in improved immune surveillance and tumor control. We propose the induction of constitutive GSK3β activity as a novel therapeutic means to bolster DC functionality in the tumor microenvironment.
在癌症患者中，树突状细胞 (DC) 的功能受到高水平肿瘤衍生抑制性细胞因子的阻碍，这些细胞因子干扰 DC 的发育和成熟。DC 发育不良会限制免疫检查点阻断和疫苗接种方法的疗效。干扰主要肿瘤相关抑制性细胞因子（如 IL-10 和 IL-6）受体下游的细胞内信号级联反应，可能改善 DC 的发育和激活，从而增强免疫治疗的效果。我们对由 >1000 个人类激酶肽底物组成的阵列进行了探索性功能筛选，以确定参与 DC 发育及其被 IL-10 或 IL-6 抑制的途径。激酶组底物谱磷酸化的改变表明糖原合酶激酶-3β (GSK3β) 是 DC 发育和抑制的关键激酶。GSK3β 抑制阻止了人 DC 的分化，伴随着 IL-12p70 分泌水平的降低，以及 T 细胞启动能力的降低。更重要的是，用组成型激活形式的 GSK3β 转导单核细胞可诱导对 IL-10 和黑色素瘤来源上清液的抑制作用产生抗性，从而导致 DC 发育改善，同时上调共刺激标记物，成熟 DC 中 CD83 表达水平增加，以及 IL-10 释放减少。此外，在黑色素瘤模型中，通过腺病毒介导的该途径的肿瘤内操作导致 DC 的激活和募集，以及改善免疫监测和肿瘤控制。我们提出诱导组成型 GSK3β 活性作为一种新的治疗手段，以增强肿瘤微环境中 DC 的功能。
