肿瘤细胞治疗研究
英文原题：The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation.
小泛素样修饰蛋白（SUMO）是泛素样蛋白超家族的一员。
小泛素样修饰蛋白（SUMO）是泛素样蛋白超家族的一员。SUMO化是一种可逆的翻译后修饰，已被认为参与调控多种细胞过程，包括炎症反应和1型干扰素（IFN1）的表达。在本报告中，我们探讨了选择性小分子SUMO化抑制剂subasumstat（TAK-981）在促进抗肿瘤先天免疫反应中的活性。我们证明，TAK-981处理可导致IFN1依赖性巨噬细胞和自然杀伤（NK）细胞活化，在离体实验中促进巨噬细胞吞噬作用和NK细胞细胞毒性。此外，TAK-981预处理与抗CD20抗体利妥昔单抗联合可增强巨噬细胞吞噬作用或NK细胞对CD20+靶细胞的细胞毒性。体内研究证明，TAK-981与利妥昔单抗在CD20+淋巴瘤异种移植模型中具有增强的抗肿瘤活性。TAK-981与抗CD38抗体daratumumab联合也导致抗肿瘤活性增强。TAK-981目前正在1期临床试验（#NCT03648372、#NCT04074330、#NCT04776018和#NCT04381650；www.clinicaltrials.gov）中研究用于治疗淋巴瘤和实体瘤患者。
Small ubiquitin-like modifier (SUMO) is a member of a ubiquitin-like protein superfamily. SUMOylation is a reversible posttranslational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of type 1 interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor subasumstat (TAK-981) in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and natural killer (NK) cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pretreatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20+ target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated enhanced antitumor activity of TAK-981 and rituximab in CD20+ lymphoma xenograft models. Combination of TAK-981 with anti-CD38 antibody daratumumab also resulted in enhanced antitumor activity. TAK-981 is currently being studied in phase 1 clinical trials (#NCT03648372, #NCT04074330, #NCT04776018, and #NCT04381650; www.clinicaltrials.gov) for the treatment of patients with lymphomas and solid tumors.
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