Htwe Khin Su Su, Soontrapa Kitipong, Prasopporn Sunisa, Chusorn Porncheera, Okada Seiji, Jirawatnotai Siwanon, Sampattavanich Somponnat, Wongkajornsilp Adisak
Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok Noi, Bangkok 10700, Thailand; Siriraj Center of Research Excellence for Systems Pharmacology (SiSP), Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok Noi, Bangkok 10700, Thailand.
Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok Noi, Bangkok 10700, Thailand.
Biomed Pharmacother. 2025 May;186:117964. doi: 10.1016/j.biopha.2025.117964. Epub 2025 Mar 18.
In this study, we explored the potential of histone deacetylase (HDAC) inhibitors, with a focus on Vorinostat, to restore the functionality of invariant natural killer T (iNKT) cells-a unique subset of T cells with potent anti-tumor activity that are often impaired within the tumor microenvironment. Using aggressive cholangiocarcinoma (CCA) cell lines lacking CD1d molecules, we observed a marked decline in iNKT cell reactivity within 48 h of exposure to CCA cells. Through a systematic approach that included the utilization of the L1000FWD search engine, Vorinostat emerged as a promising candidate for mitigating iNKT cell dysfunction. Vorinostat induced significant molecular alterations in iNKT-nonresponsive CCA cells, enhancing CD1d expression, the production of inflammatory cytokines and the activation of T cell receptor (TCR) signaling pathways. These changes effectively reactivated iNKT cells and restored their anti-tumor functionality. In the mouse xenograft model, combined treatment with Vorinostat significantly inhibited tumor growth. These findings suggest that Vorinostat may offer a novel therapeutic strategy for patients with cholangiocarcinoma who are resistant to conventional chemotherapy.
在本研究中，我们探讨了组蛋白去乙酰化酶（HDAC）抑制剂的潜力，重点关注伏立诺他，以恢复不变自然杀伤T（iNKT）细胞的功能——iNKT细胞是T细胞的一个独特亚群，具有强大的抗肿瘤活性，但在肿瘤微环境中常受到损害。使用缺乏CD1d分子的侵袭性胆管癌（CCA）细胞系，我们观察到在暴露于CCA细胞48小时内，iNKT细胞反应性显著下降。通过一种包括利用L1000FWD搜索引擎的系统方法，伏立诺他成为减轻iNKT细胞功能障碍的一个有前景的候选药物。伏立诺他在对iNKT细胞无反应的CCA细胞中诱导了显著的分子改变，增强了CD1d表达、炎性细胞因子的产生以及T细胞受体（TCR）信号通路的激活。这些变化有效地重新激活了iNKT细胞并恢复了它们的抗肿瘤功能。在小鼠异种移植模型中，伏立诺他联合治疗显著抑制了肿瘤生长。这些发现表明，伏立诺他可能为对传统化疗耐药的胆管癌患者提供一种新的治疗策略。
