National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Exp Med. 2022 Jan 3;219(1). doi: 10.1084/jem.20210789. Epub 2021 Nov 26.
Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.
靶向治疗是免疫检查点阻断（ICB）的有吸引力的联合治疗伙伴，可以增加受益的患者群体，或阻断耐药性的出现。我们证明，靶向 WEE1 通过双链 RNA（dsRNA）病毒防御途径上调免疫信号，随后对免疫检查点阻断有反应，即使在 cGAS/STING 缺陷型肿瘤中也是如此，这是多种癌症类型的典型表型。WEE1 抑制通过下调 FOXM1 来解除 SETDB1/H3K9me3 的抑制，从而增加内源性逆转录病毒元件（ERVs）的表达。ERVs 引发 dsRNA 应激和干扰素反应，增加抗肿瘤 T 细胞的募集，并在多种肿瘤模型中同时上调 PD-L1。此外，WEE1 抑制和 PD-L1 阻断联合使用以 CD8+ T 细胞依赖的方式引起显著的肿瘤消退。WEE1 抑制诱导的病毒防御特征为 WEE1 和 ICB 联合治疗的患者选择提供了一个潜在的信息生物标志物。WEE1 抑制刺激抗肿瘤免疫，并增强对 ICB 的敏感性，为临床试验中 WEE1 抑制剂和 ICB 的联合提供了依据。
