DataSheet_1_Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model.pdf

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）类癌症免疫治疗通常具有抵抗性。病毒消融疗法已被证明与ICB具有协同作用。在本研究中，我们探究了抗PD-1与病毒性麻疹疫苗在免疫能力移植性PDAC小鼠模型中的联合应用。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T细胞进行表征。此外，我们对肿瘤样本在基线、治疗期间及肿瘤进展时的基因表达进行了分析。进一步，我们分析了全身性的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，肿瘤浸润免疫细胞数量增加。基因表达分析揭示了联合治疗后免疫激活的独特但短暂的标志。然而，病毒疗法诱导的全身性抗肿瘤免疫在肿瘤进展时仍可检测到。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，为进一步发挥该方法的潜力并实现持久疗效，可能需要对其做进一步的优化。