WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway.
WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway.
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WEE1 抑制通过激活 ERV 和 dsRNA 途径诱导抗肿瘤免疫
DOI：
10.1084/jem.20210789
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发表时间：
2022-01-03
期刊：
影响因子：
--
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Guo E;Xiao R;Wu Y;Lu F;Liu C;Yang B;Li X;Fu Y;Wang Z;Li Y;Huang Y;Li F;Wu X;You L;Qin T;Lu Y;Huang X;Ma D;Mills GB;Sun C;Chen G
WEE1抑制通过调节双链RNA（dsRNA）和干扰素反应来调控癌症免疫疗法的疗效，这会增加抗肿瘤T细胞的募集，同时导致程序性死亡配体1（PD-L1）表达升高。本研究为WEE1抑制剂与抗PD-L1疗法的联合策略提供了理论依据。
靶向疗法是与免疫检查点阻断（ICB）联合应用的理想选择，有望扩大受益患者群体或阻止耐药性的产生。我们证明，靶向WEE1可通过双链RNA（dsRNA）病毒防御途径上调免疫信号，即使在cGAS/STING缺陷型肿瘤中，对免疫检查点阻断也会产生后续反应，这是多种癌症类型的典型表型。WEE1抑制通过下调叉头框蛋白M1（FOXM1），解除SETDB1/H3K9me3的抑制作用，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，在多种肿瘤模型中，增加抗肿瘤T细胞的募集，同时导致PD-L1表达升高。此外，WEE1抑制与PD-L1阻断联合使用，以CD8 + T细胞依赖的方式诱导肿瘤显著消退。WEE1抑制诱导的病毒防御特征，为选择WEE1抑制剂与ICB联合治疗的患者提供了一个潜在的有价值的生物标志物。WEE1抑制可激发抗肿瘤免疫并增强对ICB的敏感性，为WEE1抑制剂与ICB在临床试验中的联合应用提供了理论依据。
WEE1 inhibition modulates the efficacy of cancer immunotherapy by regulating dsRNA and interferon responses, which increases recruitment of anti-tumor T cells with concurrent PD-L1 elevation. This study provides a rationale for combination strategies between WEE1 inhibitors and anti–PD-L1 therapies. 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.
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14.9
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Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
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影响因子：
45.3
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