Table_1_Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model.xlsx

IntroductionPancreatic 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.MethodsWe 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.ResultsCombination 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.DiscussionOur 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.

引言：胰腺导管腺癌（PDAC）对PD-1免疫检查点阻断（ICB）的癌症免疫治疗大多表现出耐药性。病毒疗法与免疫检查点阻断疗法已显示出协同作用。在本研究中，我们探讨了在免疫健全的移植性PDAC小鼠模型中，抗PD-1和溶瘤性麻疹疫苗联合治疗的方法。方法：我们通过免疫组化、流式细胞术和T细胞受体测序对肿瘤浸润性T细胞进行了表征。此外，我们还对肿瘤样本在基线、治疗后以及肿瘤进展时的基因表达谱进行了分析。进一步地，我们分析了全身抗肿瘤和抗病毒免疫。结果：与单药治疗相比，联合治疗显著延长了生存期。病毒疗法后，肿瘤浸润性免疫细胞增加。基因表达谱分析揭示了联合治疗后免疫激活的独特但短暂的表型。然而，病毒疗法诱发了全身性抗肿瘤免疫，即使在肿瘤进展时，这种免疫反应仍可检测到。抗PD-1治疗并未影响抗病毒免疫。讨论：我们的研究结果表明，病毒疗法与免疫检查点阻断疗法的联合应用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，可能需要进一步优化这一方法。