Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles
Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles
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DOI：
10.1016/j.ymthe.2021.05.015
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发表时间：
2021-10-06
影响因子：
12.4
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
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作者：
Kakiuchi, Yoshihiko;Kuroda, Shinji;Fujiwara, Toshiyoshi
细胞外囊泡（EVs）在多种细胞间通讯过程中起着重要作用。体外效应是癌症治疗中一个有趣的现象，免疫激活通常被认为是其中的主要因素。我们之前开发了一种端粒酶特异性溶瘤腺病毒，端粒溶瘤素（OBP-301），并偶尔观察到免疫缺陷小鼠局部治疗后对远端肿瘤的治疗效果。在本研究中，我们假设ev可能参与OBP-301的体外效应。经OBP-301处理的HCT116人结肠癌细胞上清分离的EVs证实含有OBP-301，其细胞毒活性（凋亡和自噬）与OBP-301相似。在双侧皮下HCT116和CT26肿瘤模型中，瘤内给药OBP-301对未直接用OBP-301治疗的肿瘤产生了有效的抗肿瘤作用，涉及含有OBP-301的肿瘤源性ev的直接介导。这表明免疫激活不是这种体外效应的主要因素。此外，肿瘤源性ev在原位HCT116直肠肿瘤中表现出高度的肿瘤趋向性，其中在直肠肿瘤局部治疗后的转移性肝肿瘤中观察到腺病毒E1A和腺病毒5型蛋白。总之，OBP-301局部治疗有可能通过肿瘤源性ev产生体外效应。
Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.