阿苯达唑通过促进泛素介导的 PD-L1 降解诱导免疫治疗反应。

Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation.

机构信息

Department of Dermatology, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Molecular Biology Research Center, Center for Medical Genetics, Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, Hunan, China.

出版信息

J Immunother Cancer. 2022 May;10(5). doi: 10.1136/jitc-2021-003819.

DOI:10.1136/jitc-2021-003819

PMID:35577504

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9115032/

Abstract

BACKGROUND

Immune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approaches with ICIs and revealing the underlying mechanisms are important goals for achieving rapid clinical transformation and application.

METHODS

The effects on antitumor immunity activity of albendazole (ABZ) and the synergistic effects of ABZ with CD73 blockade were investigated in the melanoma B16F10 and the Lewis lung cancer tumor-bearing immune-competent mice models. The mechanism of ABZ reducing PD-L1 protein level through suppressing UBQLN4 was identified and validated through immunoprecipitation-mass spectrometry and molecular methods. Bioinformatics and anti-PD-1 therapy melanoma patients samples analysis were used to assess the level of UBQLN4/PD-L1 in the therapeutic efficacy of anti-PD-1 therapy.

RESULTS

ABZ induces CD8 T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level. Mechanistically, we revealed that ABZ promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which was bound to PD-L1 and stabilized PD-L1 protein. Preclinically, genetic deletion or target inhibition of CD73 showed synergistic effects with ABZ treatment in the immune-competent mice models. Significantly, UBQLN4 and PD-L1 levels were higher in the tumor region of responders versus non-responders and correlated with better progression-free survival and overall survival in anti-PD-1 therapy melanoma patients.

CONCLUSIONS

Our findings revealed a previously unappreciated role of ABZ in antitumor immunity by inducing ubiquitin-mediated PD-L1 protein degradation, identified predictors for assessing the therapeutic efficacy of anti-PD-1 therapy, and provided novel therapeutic possibility by combination treatment of ABZ and CD73 blockade in cancers.

摘要

背景

免疫检查点抑制剂（ICIs）已越来越多地用于各种癌症患者，并显示出有效的治疗效果。然而，在多种癌症类型中，不到 40%的病例对 ICI 有反应。因此，开发与 ICI 更有效的联合方法并揭示潜在机制是实现快速临床转化和应用的重要目标。

方法

在黑色素瘤 B16F10 和 Lewis 肺癌荷瘤免疫功能正常的小鼠模型中，研究了阿苯达唑（ABZ）对抗肿瘤免疫活性的影响及其与 CD73 阻断的协同作用。通过免疫沉淀-质谱和分子方法鉴定和验证了 ABZ 通过抑制 UBQLN4 降低 PD-L1 蛋白水平的机制。生物信息学和抗 PD-1 治疗黑色素瘤患者样本分析用于评估抗 PD-1 治疗疗效中 UBQLN4/PD-L1 的水平。

结果

ABZ 诱导 CD8 T 细胞活性和随后的免疫治疗反应，与抑制 PD-L1 蛋白水平有关。从机制上讲，我们发现 ABZ 通过抑制与 PD-L1 结合并稳定 PD-L1 蛋白的 UBQLN4 ，促进 PD-L1 的泛素化降解。临床前研究表明，在免疫功能正常的小鼠模型中，CD73 的基因缺失或靶向抑制与 ABZ 治疗具有协同作用。重要的是，在对免疫检查点抑制剂有反应的患者中，肿瘤区域的 UBQLN4 和 PD-L1 水平高于无反应者，与抗 PD-1 治疗黑色素瘤患者的无进展生存期和总生存期相关更好。