De Martino Mara, Tkach Mercedes, Bruni Sofía, Rocha Darío, Mercogliano María F, Cenciarini Mauro E, Chervo María F, Proietti Cecilia J, Dingli Florent, Loew Damarys, Fernández Elmer A, Elizalde Patricia V, Piaggio Eliane, Schillaci Roxana
Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología Y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.
Institut Curie, PSL Research University, INSERM U932, Paris, France.
Oncoimmunology. 2020 Jan 29;9(1):1715767. doi: 10.1080/2162402X.2020.1715767. eCollection 2020.
Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of CD4 + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors.
信号转导和转录激活因子3（Stat3）在多种肿瘤类型中持续激活，在维持其恶性表型和免疫抑制方面发挥着重要作用。为了利用靶向Stat3的有前景的抗肿瘤活性，了解Stat3调节细胞自主和非自主过程的机制至关重要。在此，我们证明在不同癌细胞类型中关闭Stat3的持续激活会诱导衰老，从而揭示它们对Stat3的依赖性。利用Stat3沉默诱导的衰老相关分泌表型（SASP-siStat3），我们设计了一种免疫疗法。给予SASP-siStat3免疫疗法可强烈抑制三阴性乳腺癌和黑色素瘤的生长，这与CD4 + T细胞和自然杀伤（NK）细胞的激活相关。将这种免疫疗法与抗程序性死亡蛋白1（PD-1）抗体联合使用可提高荷黑色素瘤小鼠的生存率。对SASP成分的表征表明，由环磷酸鸟苷-腺苷酸合成酶DNA传感途径激活触发的I型干扰素相关介质对其免疫监视活性很重要。总体而言，我们的研究结果提供了证据，表明给予SASP-siStat3或低剂量的Stat3阻断剂将使对Stat3有依赖性的肿瘤患者受益，以释放抗肿瘤免疫反应并提高免疫检查点抑制剂的有效性。
