TY - JOUR
T1 - Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles
AU - Kakiuchi, Yoshihiko
AU - Kuroda, Shinji
AU - Kanaya, Nobuhiko
AU - Kumon, Kento
AU - Tsumura, Tomoko
AU - Hashimoto, Masashi
AU - Yagi, Chiaki
AU - Sugimoto, Ryoma
AU - Hamada, Yuki
AU - Kikuchi, Satoru
AU - Nishizaki, Masahiko
AU - Kagawa, Shunsuke
AU - Tazawa, Hiroshi
AU - Urata, Yasuo
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
The authors would like to thank Tomoko Sueishi, Tae Yamanishi, and Yuko Hoshijima for excellent technical support. This work was supported by JSPS KAKENHI (grant no. JP16K19893 to S. Kuroda) and JSPS KAKENHI (grant no. JP20K17617 to Y.K.). Y.K. and S. Kuroda designed the experiments and wrote the manuscript. Y.K. N.K. K.K. T.T. M.H. C.Y. R.S. and Y.H. conducted the experiments. S. Kuroda, S. Kikuchi, M.N. S. Kagawa, H.T. and T.F. assisted in interpretation of the results. Y.U. provided reagents, and all authors reviewed the manuscript. Y.U. is the President and CEO of Oncolys BioPharma, Inc. the manufacturer of OBP-301 (Telomelysin). H.T. and T.F. are consultants of Oncolys BioPharma, Inc. The remaining authors declare no competing interests.
Funding Information:
The authors would like to thank Tomoko Sueishi, Tae Yamanishi, and Yuko Hoshijima for excellent technical support. This work was supported by JSPS KAKENHI (grant no. JP16K19893 to S. Kuroda) and JSPS KAKENHI (grant no. JP20K17617 to Y.K.).
Publisher Copyright:
© 2021 The American Society of Gene and Cell Therapy
PY - 2021/10/6
Y1 - 2021/10/6
N2 - 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.
AB - 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.
KW - abscopal effect
KW - drug delivery system
KW - exosome
KW - extracellular vesicles
KW - local treatment
KW - oncolytic adenovirus
KW - systemic delivery
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UR - http://www.scopus.com/inward/citedby.url?scp=85114664237&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2021.05.015
DO - 10.1016/j.ymthe.2021.05.015
M3 - Article
C2 - 34023506
AN - SCOPUS:85114664237
SN - 1525-0016
VL - 29
SP - 2920
EP - 2930
JO - Molecular Therapy
JF - Molecular Therapy
IS - 10
ER -
