PDF(Pubmed)
Abstract：
Natural killer cells (NK) are the \"professional killer\" of tumors and play a crucial role in anti-tumor immunotherapy. NK cell desensitization is a key mechanism of tumor immune escape. Dysregulated NKG2D-NKG2DL signaling is a primary driver of this desensitization process. However, the factors that regulate NK cell desensitization remain largely uncharacterized. Here, we present the first report that circular RNA circARAP2 (hsa_circ_0069396) is involved in the soluble MICA (sMICA)-induced NKG2D endocytosis in the NK cell desensitization model. CircARAP2 was upregulated during NK cell desensitization and the loss of circARAP2 alleviated NKG2D endocytosis and NK cell desensitization. Using Chromatin isolation by RNA purification (ChIRP) and RNA pull-down approaches, we identified that RAB5A, a molecular marker of early endosomes, was its downstream target. Notably, transcription factor CTCF was an intermediate functional partner of circARAP2. Mechanistically, we discovered that circARAP2 interacted with CTCF and inhibited the recruitment of CTCF-Polycomb Repressive Complex 2 (PRC2) to the promoter region of RAB5A, thereby erasing histone H3K27 and H3K9 methylation suppression to enhance RAB5A transcription. These data demonstrate that inhibition of circARAP2 effectively alleviates sMICA-induced NKG2D endocytosis and NK cell desensitization, providing a novel target for therapeutic intervention in tumor immune evasion.
摘要：
自然杀伤细胞（NK）是肿瘤的“职业杀手”，在抗肿瘤免疫治疗中起着至关重要的作用。NK细胞脱敏是肿瘤免疫逃逸的一个症结机制。失调的NKG2D-NKG2DL信号传导是这种脱敏过程的主要驱动因素。然而,调节NK细胞脱敏的因素在很大程度上仍未表征。这里,我们首次报道了环状RNAcircARAP2（hsa_circ_0069396）参与NK细胞脱敏模型中可溶性MICA（sMICA）诱导的NKG2D内吞。在NK细胞脱敏过程中CircARAP2上调，CircARAP2的丢失减轻了NKG2D内吞和NK细胞脱敏。使用通过RNA纯化（ChIRP）和RNA下拉方法分离染色质，我们发现RAB5A,早期内体的分子标记，是它的下游目标。值得注意的是,转录因子CTCF是circARAP2的中间功能伴侣.机械上,我们发现circARAP2与CTCF相互作用并抑制CTCF-Polycomb阻遏复合物2（PRC2）向RAB5A启动子区的募集，从而消除组蛋白H3K27和H3K9甲基化抑制以增强RAB5A转录。这些数据表明，circARAP2的抑制有效缓解sMICA诱导的NKG2D内吞和NK细胞脱敏，为肿瘤免疫逃避的治疗干预提供了新的靶点。
