The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and links to tumor suppression remain undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson’s Disease, was epigenetically silenced in cancer and its reexpression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NF-κB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8⁺ T cell markers, lowered the expression of immune inhibitory receptors TIM3 and LAG3, and stimulated high content of the self renewal/stem cell factor, TCF1. PRKN-induced CD8⁺ T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.

中文翻译：

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Parkin 激活先天免疫并促进抗肿瘤免疫反应


先天免疫的激活和相关干扰素 （IFN） 信号转导与癌症有关，但调节因子难以捉摸，与肿瘤抑制的联系仍未确定。在这里，我们发现 Parkin 是一种在帕金森病中改变的 E3 泛素连接酶，在癌症中被表观遗传沉默，其通过临床批准的去甲基化疗法的再表达刺激了肿瘤细胞中有效 IFN 反应的转录。该途径需要 Parkin E3 泛素连接酶活性，涉及 alarmin High Mobility Group Box 1 （HMGB1） 的亚细胞运输和释放，并且与抑制 NF-κB 基因表达有关。反过来，表达 Parkin 的细胞释放一个 IFN 分泌组，该分泌组上调效应器和细胞毒性 CD8⁺ T 细胞标志物，降低免疫抑制受体 TIM3 和 LAG3 的表达，并刺激高含量的自我更新/干细胞因子 TCF1。PRKN 诱导的 CD8 ⁺ T 细胞选择性地积累在微环境中，并抑制体内转基因和同基因肿瘤生长。因此，Parkin 是一种表观遗传调控的先天免疫激活因子和双模式肿瘤抑制因子，抑制肿瘤内在的代谢和细胞侵袭特性，同时在微环境中恢复 CD8 T 细胞功能。