On May 17, Department of Dermatology of Xiangya Hospital of Central South University and the School of Life Sciences of Central South University jointly published an online original research titled “Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation” in theJournal for Immunotherapy of Cancer(IF = 13.75). This study demonstrated for the first time that albendazole (ABZ) induces immunotherapy response, and promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which is bound to PD-L1 and stabilized PD-L1 protein. We further evaluated the synergistic efficacy of ABZ in combination with CD73 blockages which is a potential strategy of combination immunotherapy for cancer treatment.
Prof. Chen Xiang, Prof. Liu Hong and Distinguished Associate Researcher Li Hui of Xiangya Hospital, Prof. Liu Jing of School of Life Sciences of Central South University and Prof. Ye Mao of Hunan University are co-corresponding authors. Doctoral student Zhu Lin, Dr. Kuang Xinwei and Dr. Zhang Guanxiong are co-first authors. This work was supported by grants from the National Key R & D Program of the Ministry of Science and Technology, Natural Science Foundation of China for outstanding Young Scholars and the Key Project of the National Natural Science Foundation of China.
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.
ABZ is an FDA-approved broad-spectrum antiparasitic agent with low toxicity and is widely used in humans and animals. Recently, ABZ has been reported to possess antitumor activity in several cancer cell types, and ABZ showedexcellent antitumor effect in a phase I clinical trial involving 36 patients with advanced cancer. Moreover, ABZ can enhance immunological responses; for example, ABZ increased the counts of CD4+ and CD8+ T cells and significantly stimulated the IFN-gamma (a Th1-type cytokine) response in mice and human patients infected with Echinococcus. However, the functions and underlying mechanism of ABZ in anti-tumor immunity remain unclear.
In this study, the team revealed that ABZ can induce an antitumor immune response, such as metastatic melanoma and NSCLC by increasing CD8+ T cell cytotoxicity. Team found that ABZ could significantly reduce the expression of tumor cell membrane PD-L1 levels. To further investigate the molecular mechanism underlying ABZ-induced ubiquitin-mediated degradation of PD-L1, the team performed immunoprecipitation coupled to mass spectrometry in A375 cells with ABZ treatment. We revealed that UBQLN4 interacts with PD-L1 and stabilizes the PD-L1 protein. ABZ induced ubiquitination and degradation of PD-L1 by reducing the expression of UBQLN4. We not only uncovered the molecular mechanisms by which ABZ promotes antitumor immunity but also, more importantly, identified UBQLN4 as a novel posttranslational regulatory molecule of PD-L1. Preclinically, we showed that ABZ had a synergistic effect with CD73 blockade in the treatment of immune-competent mice, providing a novel combination strategy for cancer immunotherapy. 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. The team observed that patients with high UBQLN4 and PD-L1 expression in the tumor region had better progression-free survival and OS. The team observed higher UBQLN4 and PD-L1 levels in the tumor region of melanoma patients who responded to anti-PD-1 therapy than in the tumor region of nonresponders, indicating that UBQLN4 and PD-L1 might be potential biomarkers for assessing and predicting the efficacy of anti-PD-1 therapy in the clinic.
