文章：

CF33 - hNIS-抗PDL1病毒启动胰腺导管腺癌增强抗PD-L1治疗

CF33-hNIS-antiPDL1 virus primes pancreatic ductal adenocarcinoma for enhanced anti-PD-L1 therapy 

原文发布日期：2021-06-09 

英文摘要：

Immunotherapeutic strategies that combine oncolytic virus (OV) and immune checkpoint inhibitors have the potential to overcome treatment resistance in pancreatic ductal adenocarcinoma (PDAC), one of the least immunogenic solid tumors. Oncolytic viral chimera, CF33-hNIS-antiPDL1 genetically modified to express anti-human PD-L1 antibody and CF33-hNIS-Δ without the anti-PD-L1 gene, were used to investigate the immunogenic effects of OVs and virus-delivered anti-PD-L1 in PDAC in vitro. Western blot, flow cytometry, and immunofluorescence microscopy were used to evaluate the effects of CF33-hNIS-Δ and IFNγ on PD-L1 upregulation in AsPC-1 and BxPC-3 cells, and CF33-hNIS-antiPDL1 production of anti-PD-L1 and surface PD-L1 blockade of AsPC-1 and BxPC-3 with or without cocultured activated T cells. The cytosolic and cell surface levels of PD-L1 in PDAC cell lines varied; only BxPC-3 showed high cell surface expression. Treatment of these cells with CF33-hNIS-Δ and IFNγ significantly upregulated PD-L1 expression and translocation of PD-L1 from the cytosol onto the cell surface. Following coculture of activated T cells and BxPC-3 with CF33-hNIS-antiPDL1, the cell surface PD-L1 blockade on BxPC-3 cells by virus-delivered anti-PD-L1 antibody increased granzyme B release and prevented virus-induced decrease of perforin release from activated CD8+ T cells. Our results suggest that CF33-IOVs can prime immune checkpoint inhibition of PDAC and enhance antitumor immune killing. 

摘要翻译： 

联合溶瘤病毒（OV）与免疫检查点抑制剂的免疫治疗策略有望克服胰腺导管腺癌（PDAC）——这种免疫原性最弱的实体瘤之一的治疗耐药性问题。本研究采用经基因改造表达抗人PD-L1抗体的溶瘤病毒嵌合体CF33-hNIS-antiPDL1，以及不携带抗PD-L1基因的CF33-hNIS-Δ，在体外探究溶瘤病毒及病毒递送的抗PD-L1抗体对PDAC的免疫调节效应。通过蛋白质印迹、流式细胞术和免疫荧光显微镜技术，我们评估了CF33-hNIS-Δ与IFNγ对AsPC-1和BxPC-3细胞PD-L1上调的影响，检测了CF33-hNIS-antiPDL1抗PD-L1抗体的表达情况，并分析了在共培养活化T细胞条件下病毒对AsPC-1和BxPC-3细胞表面PD-L1的阻断作用。PDAC细胞系中PD-L1的胞内与细胞表面表达水平存在差异：仅BxPC-3呈现高细胞表面表达。CF33-hNIS-Δ与IFNγ处理可显著上调PD-L1表达并促进其从胞质向细胞表面转位。当活化T细胞与BxPC-3经CF33-hNIS-antiPDL1共培养后，病毒递送的抗PD-L1抗体对BxPC-3细胞表面PD-L1的阻断作用增强了颗粒酶B的释放，并阻止了病毒诱导的活化CD8+T细胞穿孔素释放减少。本研究结果表明CF33-IOVs能启动PDAC的免疫检查点抑制并增强抗肿瘤免疫杀伤效应。

原文链接：

CF33-hNIS-antiPDL1 virus primes pancreatic ductal adenocarcinoma for enhanced anti-PD-L1 therapy