Jazowiecka-Rakus Joanna, Hadrys Agata, Rahman Masmudur M, McFadden Grant, Fidyk Wojciech, Chmielik Ewa, Pazdzior Marlena, Grajek Maciej, Kozik Violetta, Sochanik Aleksander
Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze AK 15, 44-102 Gliwice, Poland.
Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland.
Cancers (Basel). 2021 Mar 19;13(6):1394. doi: 10.3390/cancers13061394.
Pancreatic ductal adenocarcinoma (PDAC) is a weakly immunogenic fatal neoplasm. Oncolytic viruses with dual anti-cancer properties-oncolytic and immune response-boosting effects-have great potential for PDAC management. Adipose-derived stem cells (ADSCs) of mesenchymal origin were infected ex vivo with recombinant myxoma virus (MYXV), which encodes murine LIGHT, also called tumor necrosis factor ligand superfamily member 14 (TNFSF14). The viability and proliferation of ADSCs were not remarkably decreased (1-2 days) following MYXV infection, in sharp contrast to cells of pancreatic carcinoma lines studied, which were rapidly killed by the infection. Comparison of the intraperitoneal (IP) vs. the intravenous (IV) route of ADSC/MYXV administration revealed more pancreas-targeted distribution of the virus when ADSCs were delivered IP to mice bearing orthotopically injected PDAC. The biodistribution, tumor burden reduction and anti-tumor adaptive immune response were examined. Bioluminescence data, used to assess the presence of the luciferase-tagged virus after IP injection, indicated enhanced trafficking into the pancreata of mice bearing orthotopically-induced PDAC, as compared to tumor-free animals, resulting in extended survival of the treated PDAC-seeded animals and in the boosted expression of key adaptive immune response markers. We conclude that ADSCs pre-loaded with transgene-armed MYXV and administered IP allow for the effective ferrying of the oncolytic virus to sites of PDAC and mediate improved tumor regression.
胰腺导管腺癌（PDAC）是一种免疫原性较弱的致命性肿瘤。具有双重抗癌特性（溶瘤和增强免疫反应作用）的溶瘤病毒在PDAC治疗中具有巨大潜力。间充质来源的脂肪干细胞（ADSCs）在体外被重组黏液瘤病毒（MYXV）感染，该病毒编码鼠LIGHT，也称为肿瘤坏死因子配体超家族成员14（TNFSF14）。与所研究的胰腺癌细胞系的细胞被感染后迅速死亡形成鲜明对比的是，ADSCs在被MYXV感染后（1 - 2天）活力和增殖并未显著降低。比较腹腔内（IP）与静脉内（IV）给予ADSC/MYXV的途径发现，当将ADSCs经腹腔注射给原位注射了PDAC的小鼠时，病毒在胰腺中的靶向分布更多。对生物分布、肿瘤负荷减轻和抗肿瘤适应性免疫反应进行了检测。用于评估腹腔注射后荧光素酶标记病毒存在情况的生物发光数据表明，与无肿瘤动物相比，原位诱导PDAC的小鼠胰腺中病毒的转运增强，导致接受治疗的接种PDAC的动物生存期延长，关键适应性免疫反应标志物的表达增强。我们得出结论，预先装载有携带转基因的MYXV并经腹腔注射的ADSCs能够有效地将溶瘤病毒运送到PDAC部位，并介导更好的肿瘤消退。
