Melanoma and Sarcoma Medical Oncology Unit, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, PR China.
Department of Pediatric Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, PR China.
Clin Exp Immunol. 2022 Aug 19;209(2):127-139. doi: 10.1093/cei/uxac068.
Sarcoma is a rare and heterogeneous class of mesenchymal malignancies with poor prognosis. Panobinostat (LBH589) as one of histone deacetylase (HDAC) inhibitors has demonstrated anti-tumor activity in patients with sarcoma, but its mechanisms remains unclear. Here, we found that LBH589 alone inhibited the proliferation and colony formation of soft tissue sarcoma (STS) cell lines. Transcriptome analysis showed that treatment with LBH589 augmented the NK cell-mediated cytotoxicity. Quantitative real-time PCR and flow cytometric analysis (FACS) further confirmed that LBH589 increased the expression of NKG2D ligands MICA/MICB. Mechanistically, LBH589 activated the Wnt/β-catenin pathway by upregulating the histone acetylation in β-catenin promoter. In vitro co-culture experiments and in vivo animal experiments showed that LBH589 increased the cytotoxicity of natural killer (NK) cells while Wnt/β-catenin inhibitor decreased the effects. Our findings suggest that LBH589 facilitates the anti-tumor effect of NK cells, highlights LBH589 an effective assistance drug in NK cell-based immunotherapies.
肉瘤是一种罕见且异质性的间充质恶性肿瘤，预后不良。帕比司他（LBH589）作为组蛋白去乙酰化酶（HDAC）抑制剂之一，已在肉瘤患者中显示出抗肿瘤活性，但其机制尚不清楚。在这里，我们发现 LBH589 单独抑制软组织肉瘤（STS）细胞系的增殖和集落形成。转录组分析表明，LBH589 处理增强了 NK 细胞介导的细胞毒性。实时定量 PCR 和流式细胞术（FACS）分析进一步证实，LBH589 增加了 NKG2D 配体 MICA/MICB 的表达。在机制上，LBH589 通过上调 β-连环蛋白启动子中的组蛋白乙酰化来激活 Wnt/β-连环蛋白通路。体外共培养实验和体内动物实验表明，LBH589 增加了自然杀伤（NK）细胞的细胞毒性，而 Wnt/β-连环蛋白抑制剂则降低了这种作用。我们的研究结果表明，LBH589 促进了 NK 细胞的抗肿瘤作用，凸显了 LBH589 在 NK 细胞为基础的免疫治疗中的有效辅助药物作用。
