文章：

MTH1抑制缓解免疫抑制并增强抗PD-L1免疫疗法在实验性间皮瘤中的疗效

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma

原文发布日期：12 October 2023

DOI: 10.3390/cancers15204962

类型: Article

开放获取: 是

英文摘要：

Background: MTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens. Methods: Our hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players. Results: Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy. Conclusions: Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma.

摘要翻译： 

背景：MTH1通过保护肿瘤细胞及其支持性内皮细胞免受肿瘤微环境中氧化应激引发的致死性DNA损伤，从而促进肿瘤生长。MTH1对肿瘤相关免疫区室的影响尚不明确。我们假设MTH1能够调节免疫功能，从而增强现有免疫治疗方案的效果。 方法：我们使用临床相关的MTH1抑制剂karonudib，在两个同基因小鼠间皮瘤模型中验证了该假设。同时研究了MTH1与PD-L1联合阻断对间皮瘤进展的影响，重点关注主要免疫细胞亚群。 结果：Karonudib给药可增强M1型巨噬细胞极化，刺激CD8+ T细胞扩增，并促进树突状细胞和T细胞的活化。与单药治疗相比，PD-L1与MTH1抑制剂联合给药能更有效地抑制间皮瘤生长和胸膜积液积聚。 结论：MTH1与PD-L1联合抑制有望为间皮瘤的临床治疗提供新策略。

原文链接：

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma