Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Cell Death Dis. 2021 Mar 17;12(4):282. doi: 10.1038/s41419-021-03556-4.
Anti-CD47/PD-L1 immunotherapies aiming to enhance antitumor immunity are being intensively investigated and show promising results in cancer therapy; however, not all patients treated with these new drugs respond. Thus, developing new immunotherapy agents or combination treatments to enhance the efficacy of immunotherapy is an urgent challenge. Here, we found that LSD1 knockdown directly downregulated the expression of CD47 and PD-L1 through upregulating H3K4me2 levels in the CD47 and CD274 promoter regions. In addition, the LSD1/wild-type p53/miR-34a signaling axis was also involved in the regulation of CD47/PD-L1 expression by targeting the 3' untranslated regions (3'UTRs) of CD47/PD-L1. Further, the results showed that an LSD1 inhibitor (ORY-1001) combined with anti-CD47/PD-L1 monoclonal antibodies inhibited tumor growth in an established subcutaneous xenograft model more effectively than a single blockade strategy. Collectively, these findings indicate that LSD1 inhibition enhances the therapeutic efficacy of PD-L1/CD47 blockade by reducing CD47 and PD-L1 expression in cervical cancer.
抗 CD47/PD-L1 免疫疗法旨在增强抗肿瘤免疫，正在癌症治疗中得到深入研究，并显示出有前景的结果；然而，并非所有接受这些新药治疗的患者都有反应。因此，开发新的免疫治疗药物或联合治疗以提高免疫疗法的疗效是一个紧迫的挑战。在这里，我们发现 LSD1 敲低通过上调 CD47 和 CD274 启动子区域的 H3K4me2 水平直接下调 CD47 和 PD-L1 的表达。此外，LSD1/野生型 p53/miR-34a 信号轴也通过靶向 CD47/PD-L1 的 3'非翻译区（3'UTR）参与 CD47/PD-L1 表达的调节。进一步的研究结果表明，LSD1 抑制剂（ORY-1001）与抗 CD47/PD-L1 单克隆抗体联合使用，比单一阻断策略更有效地抑制了已建立的皮下异种移植模型中的肿瘤生长。总的来说，这些发现表明 LSD1 抑制通过降低宫颈癌中 CD47 和 PD-L1 的表达，增强了 PD-L1/CD47 阻断的治疗效果。
