Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Faculty of Health, School of Medicine, Center for Biomedical Research and Education (ZBAF), Institute of Virology and Microbiology, Witten/Herdecke University, Witten, Germany.
Front Immunol. 2023 Jan 16;13:1096162. doi: 10.3389/fimmu.2022.1096162. eCollection 2022.
Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to cancer immunotherapy with PD-1 immune checkpoint blockade (ICB). Oncolytic virotherapy has been shown to synergize with ICB. In this work, we investigated the combination of anti-PD-1 and oncolytic measles vaccine in an immunocompetent transplantable PDAC mouse model.
We characterized tumor-infiltrating T cells by immunohistochemistry, flow cytometry and T cell receptor sequencing. Further, we performed gene expression profiling of tumor samples at baseline, after treatment, and when tumors progressed. Moreover, we analyzed systemic anti-tumor and anti-viral immunity.
Combination treatment significantly prolonged survival compared to monotherapies. Tumor-infiltrating immune cells were increased after virotherapy. Gene expression profiling revealed a unique, but transient signature of immune activation after combination treatment. However, systemic anti-tumor immunity was induced by virotherapy and remained detectable even when tumors progressed. Anti-PD-1 treatment did not impact anti-viral immunity.
Our results indicate that combined virotherapy and ICB induces anti-tumor immunity and reshapes the tumor immune environment. However, further refinement of this approach may be required to develop its full potential and achieve durable efficacy.
胰腺导管腺癌 (PDAC) 对 PD-1 免疫检查点阻断 (ICB) 的癌症免疫疗法大多具有抗性。溶瘤病毒疗法已被证明与 ICB 具有协同作用。在这项工作中，我们在免疫功能正常的可移植 PDAC 小鼠模型中研究了抗 PD-1 和溶瘤麻疹疫苗的联合应用。
我们通过免疫组织化学、流式细胞术和 T 细胞受体测序来描述肿瘤浸润 T 细胞。此外，我们对基线时、治疗后和肿瘤进展时的肿瘤样本进行了基因表达谱分析。此外，我们还分析了系统的抗肿瘤和抗病毒免疫。
与单药治疗相比，联合治疗显著延长了生存时间。病毒治疗后肿瘤浸润免疫细胞增加。基因表达谱分析显示，联合治疗后出现了独特但短暂的免疫激活特征。然而，病毒治疗诱导了系统的抗肿瘤免疫，即使肿瘤进展，这种免疫仍可检测到。抗 PD-1 治疗并未影响抗病毒免疫。
我们的结果表明，溶瘤病毒联合 ICB 可诱导抗肿瘤免疫并重塑肿瘤免疫微环境。然而，为了充分发挥其潜力并实现持久疗效，可能需要进一步改进这种方法。
