Department of Biochemistry & Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.
Nat Commun. 2023 Jul 10;14(1):4066. doi: 10.1038/s41467-023-39920-5.
Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy.
尽管癌症治疗取得了进展，但免疫检查点阻断（ICB）仅在一些患者中实现完全缓解，这表明需要确定耐药机制。在这里，我们使用一种对 ICB 不敏感的肿瘤模型发现，顺铂增强了 PD-L1 阻断的抗肿瘤作用，并上调了肿瘤中 Ariadne RBR E3 泛素蛋白连接酶 1（ARIH1）的表达。Arih1 过表达促进细胞毒性 T 细胞浸润，抑制肿瘤生长，并增强 PD-L1 阻断作用。ARIH1 介导 DNA-PKcs 的泛素化和降解，从而触发 STING 途径的激活，该途径被 cGAS 蛋白的磷酸模拟突变体 T68E/S213D 阻断。通过高通量药物筛选，我们进一步发现，ACY738 的细胞毒性比顺铂低，能有效上调 ARIH1 并激活 STING 信号，使肿瘤对 PD-L1 阻断敏感。我们的研究结果描绘了一种机制，即肿瘤通过失去 ARIH1 和 ARIH1-DNA-PKcs-STING 信号来介导 ICB 耐药，并表明激活 ARIH1 是提高癌症免疫治疗疗效的有效策略。
