Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, and.
Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
JCI Insight. 2020 Jun 4;5(11):137569. doi: 10.1172/jci.insight.137569.
Recently, we reported that expression of endogenous retroviruses (ERVs) is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). We show that decitabine, a DNA hypomethylating agent, activates transposable element (TE) expression (LINE1 and ERVs ERV3-2 and ERV4700) and antiviral signaling to potentially enhance response to ICB in kidney cancer cell lines and primary cells. KO of RIGI and MDA5 dsRNA sensors attenuated activation of antiviral signaling associated with DNA hypomethylation, and RIGI and MDA5 IPs showed increased ERV binding with decitabine treatment. Bioinformatic analyses showed the decitabine-induced signature could be associated with increased immune infiltration and response to ICB. Cytokine secretion induced by decitabine could modestly improve T cell activation and robustly enhanced T cell migration. In a small retrospective cohort of metastatic clear cell RCC (ccRCC) patients treated with anti-PD1/PDL1 blockade, activation of some antiviral genes was significantly higher in responders. Thus, we identified a potential strategy to induce TE expression through inhibition of DNA methylation in modulating T cell action via regulation of the innate antiviral pathway.
最近，我们报道了内源性逆转录病毒（ERVs）的表达与肾细胞癌（RCC）对免疫检查点阻断（ICB）的反应有关。我们表明，去甲基化剂地西他滨激活转座元件（TE）的表达（LINE1 和 ERV3-2 和 ERV4700）和抗病毒信号，可能增强肾癌细胞系和原代细胞对 ICB 的反应。RIGI 和 MDA5 dsRNA 传感器的 KO 减弱了与 DNA 去甲基化相关的抗病毒信号的激活，并且 RIGI 和 MDA5 IP 在接受地西他滨治疗时显示出增加的 ERV 结合。生物信息学分析表明，地西他滨诱导的特征可能与免疫浸润增加和对 ICB 的反应相关。地西他滨诱导的细胞因子分泌可适度改善 T 细胞激活，并强烈增强 T 细胞迁移。在接受抗 PD1/PDL1 阻断治疗的转移性透明细胞肾细胞癌（ccRCC）患者的小回顾性队列中，应答者中一些抗病毒基因的激活明显更高。因此，我们确定了一种通过抑制 DNA 甲基化来诱导 TE 表达的潜在策略，通过调节先天抗病毒途径来调节 T 细胞作用。
