Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity
Abstract Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and...
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| Format: | Article |
| Language: | English |
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Springer
2024-11-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-024-03849-5 |
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| author | Tomoko Ohtani Shinji Kuroda Nobuhiko Kanaya Yoshihiko Kakiuchi Kento Kumon Masashi Hashimoto Chiaki Yagi Ryoma Sugimoto Satoru Kikuchi Shunsuke Kagawa Hiroshi Tazawa Yasuo Urata Toshiyoshi Fujiwara |
| author_facet | Tomoko Ohtani Shinji Kuroda Nobuhiko Kanaya Yoshihiko Kakiuchi Kento Kumon Masashi Hashimoto Chiaki Yagi Ryoma Sugimoto Satoru Kikuchi Shunsuke Kagawa Hiroshi Tazawa Yasuo Urata Toshiyoshi Fujiwara |
| author_sort | Tomoko Ohtani |
| collection | DOAJ |
| description | Abstract Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect. |
| format | Article |
| id | doaj-art-c554f7f7d8c5430eab0ce7563ff51b34 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-c554f7f7d8c5430eab0ce7563ff51b342025-02-02T12:26:47ZengSpringerCancer Immunology, Immunotherapy1432-08512024-11-0174111210.1007/s00262-024-03849-5Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunityTomoko Ohtani0Shinji Kuroda1Nobuhiko Kanaya2Yoshihiko Kakiuchi3Kento Kumon4Masashi Hashimoto5Chiaki Yagi6Ryoma Sugimoto7Satoru Kikuchi8Shunsuke Kagawa9Hiroshi Tazawa10Yasuo Urata11Toshiyoshi Fujiwara12Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOncolys BioPharma, IncDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAbstract Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.https://doi.org/10.1007/s00262-024-03849-5Oncolytic adenovirusp53Dendritic cellsAnti-tumor immunityExosome |
| spellingShingle | Tomoko Ohtani Shinji Kuroda Nobuhiko Kanaya Yoshihiko Kakiuchi Kento Kumon Masashi Hashimoto Chiaki Yagi Ryoma Sugimoto Satoru Kikuchi Shunsuke Kagawa Hiroshi Tazawa Yasuo Urata Toshiyoshi Fujiwara Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity Cancer Immunology, Immunotherapy Oncolytic adenovirus p53 Dendritic cells Anti-tumor immunity Exosome |
| title | Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity |
| title_full | Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity |
| title_fullStr | Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity |
| title_full_unstemmed | Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity |
| title_short | Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity |
| title_sort | dendritic cell maturation is induced by p53 armed oncolytic adenovirus via tumor derived exosomes enhancing systemic antitumor immunity |
| topic | Oncolytic adenovirus p53 Dendritic cells Anti-tumor immunity Exosome |
| url | https://doi.org/10.1007/s00262-024-03849-5 |
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