Abstract:
The present study aimed to clarify the hypothesis that auger emitter 125I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression by promoting antitumor immune response. Pancreatic cancer cell line (Panc02) and mice subcutaneously inoculated with Panc02 cells were employed for the in vitro and in vivo experiments, respectively, followed by 125I and Olaparib administrations. The apoptosis and CRT exposure of Panc02 cells were detected using flow cytometry assay. QRT-PCR, immunofluorescence, immunohistochemical analysis, and western blot were employed to examine mRNA and protein expression. Experimental results showed that 125I combined with Olaparib induced immunogenic cell death and affected antigen presentation in pancreatic cancer. 125I in combination with Olaparib influenced T cells and dendritic cells by up-regulating CD4, CD8, CD69, Caspase3, CD86, granzyme B, CD80, and type I interferon (IFN)-γ and down-regulating Ki67 in vivo. The combination also activated the cyclic GMP-AMP synthase stimulator of IFN genes (Sting) pathway in Panc02 cells. Moreover, Sting knockdown alleviated the effect of the combination of 125I and Olaparib on pancreatic cancer progression. In summary, 125I in combination with Olaparib inhibited pancreatic cancer progression through promoting antitumor immune responses, which may provide a potential treatment for pancreatic cancer.
摘要:
本研究旨在阐明以下假设:螺旋发射器125I颗粒与PARP抑制剂Olaparib组合可通过促进抗肿瘤免疫反应来抑制胰腺癌进展。胰腺癌细胞系(Panc02)和皮下接种Panc02细胞的小鼠用于体外和体内实验。分别,其次是125I和Olaparib管理。流式细胞术检测Panc02细胞的凋亡和CRT暴露。QRT-PCR,免疫荧光,免疫组织化学分析,采用Westernblot检测mRNA和蛋白表达。实验结果表明,125I联合奥拉帕尼诱导胰腺癌免疫原性细胞死亡并影响抗原呈递。125I联合奥拉帕尼通过上调CD4,CD8,CD69,Caspase3,CD86,颗粒酶B影响T细胞和树突状细胞,CD80和I型干扰素(IFN)-γ在体内下调Ki67。该组合还激活了Panc02细胞中IFN基因(Sting)途径的环状GMP-AMP合酶刺激物。此外,Sting敲除减轻了125I和Olaparib的组合对胰腺癌进展的影响。总之,125I联合奥拉帕尼通过促进抗肿瘤免疫反应抑制胰腺癌进展,这可能为胰腺癌提供潜在的治疗方法。