Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Mol Cell. 2020 Jun 18;78(6):1207-1223.e8. doi: 10.1016/j.molcel.2020.05.015. Epub 2020 Jun 5.
Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.
肿瘤干扰素 (IFN) 信号促进 PD-L1 表达以抑制 T 细胞介导的免疫监视。我们鉴定出 IFN 刺激的非编码 RNA 1 (INCR1) 是一种从 PD-L1 基因座转录的长非编码 RNA (lncRNA)，并表明 INCR1 控制多种肿瘤类型中的 IFNγ 信号。沉默 INCR1 会降低 PD-L1、JAK2 和其他几种 IFNγ 刺激基因的表达。INCR1 敲低可使肿瘤细胞对细胞毒性 T 细胞介导的杀伤敏感，从而改善 CAR T 细胞疗法。我们发现 PD-L1 和 JAK2 转录本通过与核核糖核蛋白 HNRNPH1 结合而受到负调控。INCR1 的初级转录本与 HNRNPH1 结合，以阻止其对邻近基因 PD-L1 和 JAK2 的抑制作用，从而使其表达。这些发现介绍了由 lncRNA INCR1 介导的肿瘤 IFNγ 信号调节的机制，并为癌症免疫治疗提供了一个治疗靶点。
