Chen Kang, Dai Manxiong, Luo Quanneng, Wang Yi, Shen Weitao, Liao Yan, Zhou Yiying, Cheng Wei
Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410005, Hunan Province, China; Translational Medicine Laboratory of Pancreas Disease of Hunan Normal University, Changsha 410005, Hunan Province, China.
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Int J Biochem Cell Biol. 2023 Feb;155:106358. doi: 10.1016/j.biocel.2022.106358. Epub 2022 Dec 28.
The PARP1 protein plays a key role in DNA damage repair and ADP-ribosylation to regulate gene expression. Strategies to target PARP1 have rapidly been developed for cancer treatment. However, the role of the innate immune response in targeted anti-PARP1 therapy remains poorly understood. In this work, we aimed to elucidate the regulatory mechanism underlying the immunogenicity of PARP1 and explore efficient therapeutic strategies to enhance the antitumor effect of PARP inhibitors. The relationships between PARP1 expression and immunosuppressive factors were examined by qRTPCR and immunoblot analysis. DNA pull-down, chromatin immunoprecipitation-quantitative PCR (ChIPqPCR) and luciferase reporter assays were employed to reveal the mechanism by which the expression of the immune checkpoint regulator CD24 is regulated by PARP1. Phagocytosis assays and pancreatic cancer animal models were applied to evaluate the therapeutic effect of simultaneous disruption of PARP1 and the antiphagocytic factor CD24. Upregulation of the innate immunosuppressive factor CD24 was observed in pancreatic cancer during PARP1 inhibition. The activating effect of targeting CD24 on macrophage phagocytosis was verified. Then, we showed that PARP1 attenuated the transcription of CD24 by ADP-ribosylating the transcription factor DDX5 in pancreatic cancer. Combined blockade of PARP1 and the antiphagocytic factor CD24 elicited a synergetic antitumor effect in pancreatic cancer. Our research provided evidence that combination treatment with PARP inhibitors and CD24 blocking monoclonal antibodies (mAbs) could be an effective strategy to improve the clinical therapeutic response in pancreatic cancer.
PARP1蛋白在DNA损伤修复和ADP核糖基化以调节基因表达方面发挥着关键作用。针对PARP1的靶向治疗策略已迅速开发用于癌症治疗。然而，先天免疫反应在靶向抗PARP1治疗中的作用仍知之甚少。在这项工作中，我们旨在阐明PARP1免疫原性的调节机制，并探索提高PARP抑制剂抗肿瘤效果的有效治疗策略。通过qRTPCR和免疫印迹分析检测PARP1表达与免疫抑制因子之间的关系。采用DNA下拉、染色质免疫沉淀定量PCR（ChIP-qPCR）和荧光素酶报告基因检测来揭示PARP1调节免疫检查点调节剂CD24表达的机制。应用吞噬试验和胰腺癌动物模型来评估同时破坏PARP1和抗吞噬因子CD24的治疗效果。在PARP1抑制期间，胰腺癌中观察到先天免疫抑制因子CD24的上调。验证了靶向CD24对巨噬细胞吞噬作用的激活作用。然后，我们表明PARP1通过在胰腺癌中对转录因子DDX5进行ADP核糖基化来减弱CD24的转录。PARP1和抗吞噬因子CD24的联合阻断在胰腺癌中产生了协同抗肿瘤作用。我们的研究提供了证据，表明PARP抑制剂与CD24阻断单克隆抗体（mAb）联合治疗可能是提高胰腺癌临床治疗反应的有效策略。
