Department of Oncology, Georgetown University Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
Shuttle Pharmaceuticals, Inc., Rockville, Maryland.
Mol Cancer Ther. 2023 Dec 1;22(12):1376-1389. doi: 10.1158/1535-7163.MCT-23-0215.
Radiotherapy is a curative cancer treatment modality that imparts damage to cellular DNA, induces immunogenic cell death, and activates antitumor immunity. Despite the radiotherapy-induced direct antitumor effect seen within the treated volume, accumulating evidence indicates activation of innate antitumor immunity. Acute proinflammatory responses mediated by anticancer M1 macrophages are observed in the immediate aftermath following radiotherapy. However, after a few days, these M1 macrophages are converted to anti-inflammatory and pro-cancer M2 phenotype, leading to cancer resistance and underlying potential tumor relapse. Histone deacetylase 6 (HDAC6) plays a crucial role in regulating macrophage polarization and innate immune responses. Here, we report targeting HDAC6 function with a novel selective inhibitor (SP-2-225) as a potential therapeutic candidate for combination therapy with radiotherapy. This resulted in decreased tumor growth and enhanced M1/M2 ratio of infiltrating macrophages within tumors. These observations support the use of selective HDAC6 inhibitors to improve antitumor immune responses and prevent tumor relapse after radiotherapy.
放射疗法是一种有治愈效果的癌症治疗方式，它会对细胞 DNA 造成损伤，诱导免疫原性细胞死亡，并激活抗肿瘤免疫。尽管在接受治疗的区域内可以看到放射治疗引起的直接抗肿瘤效应，但越来越多的证据表明，先天抗肿瘤免疫被激活了。在放射治疗后立即会观察到抗癌 M1 巨噬细胞介导的急性促炎反应。然而，几天后，这些 M1 巨噬细胞会转变为抗炎和促癌 M2 表型，导致癌症耐药和潜在的肿瘤复发。组蛋白去乙酰化酶 6 (HDAC6) 在调节巨噬细胞极化和先天免疫反应方面起着至关重要的作用。在这里，我们报告了用一种新型选择性抑制剂 (SP-2-225) 靶向 HDAC6 功能作为与放射疗法联合治疗的潜在治疗候选物。这导致肿瘤生长减少，并增强了肿瘤内浸润巨噬细胞的 M1/M2 比值。这些观察结果支持使用选择性 HDAC6 抑制剂来改善抗肿瘤免疫反应，并防止放射治疗后肿瘤复发。
