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) 信号传导促进 PD-L1 表达，从而抑制 T 细胞介导的免疫监视。我们将 IFN 刺激的非编码 RNA 1 ( INCR1 ) 鉴定为从PD-L1基因座转录的长非编码 RNA (lncRNA) ，并表明INCR1在多种肿瘤类型中控制 IFNγ 信号传导。沉默INCR1会降低 PD-L1、JAK2 和其他几个 IFNγ 刺激基因的表达。INCR1敲低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转录物通过与核核糖核蛋白 HNRNPH1 结合而受到负向调节。的主要转录本INCR1与 HNRNPH1 结合，阻断其对邻近基因PD-L1和JAK2的抑制作用，从而使它们得以表达。这些发现介绍了 lncRNA INCR1介导的肿瘤 IFNγ 信号传导调节机制，并提出了癌症免疫治疗的治疗靶点。